Lithium's relationship to Alzheimer's

By Allen Yang

August 21, 2025

About this collection

This is a compilation of all the references from the paper "Lithium deficiency and the onset of Alzheimer’s disease" by Aron, Liviu et al., published August 6, 2025 in Nature. https://www.nature.com/articles/s41586-025-09335-x This knowledge base has all the publicly accessible papers in the References section of the above paper (~79 out of 90), as well as the paper itself. Ask questions here to explore this body of knowledge on lithium's impact on Alzheimer's and other neurological and mental health areas.

Curated Sources

Lithium deficiency and the onset of Alzheimer’s disease | Nature

This study investigates the role of endogenous lithium in Alzheimer's disease (AD) pathogenesis. The authors found that lithium levels were significantly reduced in the brains of individuals with mild cognitive impairment (MCI) and AD. Lithium deficiency in mouse models accelerated AD pathology, including amyloid-β deposition, tau hyperphosphorylation, and neuroinflammation. Lithium replacement therapy with a plaque-evading lithium salt, lithium orotate, prevented and reversed AD pathology and cognitive decline in AD mouse models and ageing wild-type mice. The study suggests that lithium homeostasis contributes to cognitive resilience and that disruption of lithium homeostasis may be an early event in AD pathogenesis.

Key Takeaways

Lithium deficiency is associated with Alzheimer's disease pathology and cognitive decline.
Lithium replacement therapy with lithium orotate prevents and reverses AD pathology and cognitive decline.
GSK3β regulation is a key mechanism underlying the effects of lithium deficiency on AD pathology.
Lithium homeostasis contributes to cognitive resilience in normal ageing humans and mice.

The PRIDE database at 20 years: 2025 update

The PRIDE database, a leading mass spectrometry-based proteomics data repository, celebrates its 20th anniversary with significant updates. PRIDE Archive, its archival component, has seen a substantial increase in submissions, averaging 534 datasets per month. Improvements include a new file transfer protocol (Globus), enhanced dataset resubmission and validation processes, and better support for MS crosslinking datasets. The PRIDE ecosystem now includes various resources and tools such as PRIDE USI service, PRIDE Crosslinking resource, and a chatbot based on Large Language Models. PRIDE continues to disseminate high-quality proteomics data into resources like UniProt, Ensembl, and Expression Atlas. The database has stored 42,036 datasets as of August 2024, with a total size of 2.85 Petabytes. Data reuse activities are increasing, with multiple resources reanalyzing PRIDE datasets. Future plans include enhancing metadata annotation standards, developing a controlled-access infrastructure for sensitive human proteomics data, and integrating PRIDE data into the Open Targets platform.

Key Takeaways

PRIDE database has improved data submission and validation processes with new protocols and automated workflows.
The database has expanded its ecosystem with new resources and tools, enhancing data accessibility and analysis.
PRIDE continues to play a crucial role in proteomics data dissemination and reuse, supporting various downstream applications and resources.

OPENACCESS

This study combined 3D neuronal cultures and induced pluripotent stem cell (iPSC) technology to generate 3D neuro-spheroids from Alzheimer's disease (AD) patients. The 3D neuro-spheroids were characterized and treated with BACE1 and γ-secretase inhibitors to evaluate their efficacy in reducing amyloid β (Aβ) production. The results showed that both inhibitors decreased Aβ generation in 2D neurons, but their potency was reduced in 3D cultures. Proteomic analysis revealed specific molecular signatures that affected inhibitor efficacy, including variations in APP and clathrin protein levels. The study highlights the potential of using iPSC-differentiated 3D neuronal systems for drug screening and understanding individual variations in drug response.

Key Takeaways

The 3D neuro-spheroid model recapitulates key features of Alzheimer's disease pathology, including Aβ generation and Tau pathology.
BACE1 and γ-secretase inhibitors showed reduced efficacy in 3D cultures compared to 2D neurons, likely due to reduced drug exposure.
Proteomic analysis revealed individual variations in protein levels, including APP and clathrin, that affected inhibitor efficacy.
The study highlights the importance of considering individual genetic background and cellular responses when evaluating candidate anti-amyloid therapeutics.
The 3D neuro-spheroid model provides a physiologically relevant and valid model for testing efficacy of AD drugs and understanding individual variations in drug response.

OPENACCESS

This study developed a 3D human neuro-spheroid model of Alzheimer's disease using induced pluripotent stem cells (iPSCs) derived from AD patients' blood cells. The model was characterized for neuronal markers and used to test the efficacy of BACE1 and γ-secretase inhibitors in reducing Aβ generation. The results showed that both inhibitors decreased Aβ levels in 2D and 3D cultures, but with less potency in 3D cultures. Proteomic analysis revealed differences in protein expression between subjects, which may affect inhibitor efficacy.

Key Takeaways

The 3D neuro-spheroid model recapitulates key features of Alzheimer's disease pathology and allows for testing of candidate treatments.
Variability in response to BACE1 and γ-secretase inhibitors among iPSC-derived neuronal lines suggests individualized testing may be necessary.
Reduced drug efficacy in 3D cultures compared to 2D cultures is related to decreased drug exposure within the spheroids.

Common proteomic profiles of induced pluripotent stem cellderived three-dimensional neurons and brain tissue from Alzheimer patients

This study analyzed proteomic profiles of induced pluripotent stem cell-derived three-dimensional (3D) neurons and post-mortem brain tissue from Alzheimer's disease (AD) patients. The results showed alterations in proteins involved in axon growth, mitochondrial function, and antioxidant defense in 3D neurons, and proteins related to oxidative stress, neuro-inflammation, and axonal injury in brain tissue. The study found a correlation between the proteomic profiles of 3D neurons and brain tissue, suggesting that the 3D neuronal system can be used as a model to examine novel aspects of AD pathology.

Key Takeaways

The study identified common proteomic profiles between 3D neurons and brain tissue from AD patients, including alterations in axon proteins and immune response pathways.
The 3D neuronal system can be used as a model to examine novel aspects of AD pathology and screen oxidative stress suppressors.
The absence of microglia cells in the 3D neuro-spheroids culture may explain the difference in inflammatory responses between 3D neurons and post-mortem AD brain tissue.
Vimentin was found decreased in both AD-derived 3D neuro-spheroids and post-mortem AD brain tissue, suggesting a potential role in maintaining neuronal homeostasis.

The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource

The NHGRI-EBI GWAS Catalog is a comprehensive knowledgebase providing detailed, structured, and standardized genome-wide association study (GWAS) data to over 200,000 users annually. It contains over 45,000 published GWAS across more than 5,000 human traits and 40,000 full P-value summary statistics datasets. The Catalog has expanded to include sequencing-based GWAS, gene-based analyses, and copy number variation analyses. A new author-submission system allows direct submission of GWAS summary statistics, enabling rapid access to full genome-wide datasets. The Catalog has improved trait annotation using the Experimental Factor Ontology (EFO) and enhanced integration with other resources, such as the Polygenic Score Catalog and the International Mouse Phenotyping Consortium. Efforts have been made to promote equitable data sharing, including outreach to under-represented traits and communities, and addressing barriers to data sharing.

Key Takeaways

The NHGRI-EBI GWAS Catalog has transitioned from a fully curated resource to include directly submitted GWAS summary statistics and metadata, ensuring rapid access to full genome-wide datasets.
The Catalog has expanded its scope to include new data types, such as sequencing-based GWAS and aggregate analyses, and has improved trait annotation using EFO.
Efforts to promote equitable data sharing have led to increased sharing of GWAS summary statistics, particularly in under-represented traits like cancer, and have highlighted the need to address diversity and inclusion in genomics research.

limma for differential expression analysis of RNA-seq and microarray data

The limma package is an R/Bioconductor software that provides an integrated solution for analyzing data from gene expression experiments, including RNA-seq and microarray studies. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. limma can perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data, and all the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. The package is designed to analyze both RNA-seq and microarray data with very similar pipelines, providing enhanced possibilities for biological interpretation of gene expression differences. limma integrates a number of statistical principles, including linear models, empirical Bayes methods, and variance modelling, to deliver powerful inference for differential expression analysis. The package also includes various data pre-processing and quality assessment tools, as well as methods for gene set testing and higher-level expression signature analyses.

Key Takeaways

limma's linear modelling approach allows for complex experimental designs and information borrowing between genes, making it suitable for small sample sizes.
The voom methodology enables limma to analyze RNA-seq data with high precision by converting counts to log-scale and estimating the mean-variance relationship.
limma provides a range of gene set testing methods, including camera, roast, and romer, which can be used to assess the overall significance of co-regulated gene sets and identify biologically relevant pathways.

limma for differential expression analysis of RNA-seq and microarray data

The limma package is an R/Bioconductor software that provides an integrated solution for analyzing data from gene expression experiments, including RNA-seq and microarray data. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. limma can perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data, and all the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. The package is designed to analyze both RNA-seq and microarray data with very similar pipelines, providing enhanced possibilities for biological interpretation of gene expression differences.

Key Takeaways

limma's empirical Bayes method improves statistical power and accuracy by borrowing information between genes.
The package can handle complex experimental designs and provides various normalization methods for different platforms.
limma's capabilities have been expanded to include differential splicing analysis and higher-level expression signature analyses involving co-regulated sets of genes.

Normalization of RNA-seq data using factor analysis of control genes or samples

This study evaluates the performance of various normalization methods for RNA-seq data, including the use of External RNA Control Consortium (ERCC) spike-in controls. The authors propose a novel normalization strategy, remove unwanted variation (RUV), which adjusts for nuisance technical effects by performing factor analysis on suitable sets of control genes or samples. The results show that RUV outperforms state-of-the-art normalization approaches in terms of estimating expression fold-changes and testing differential expression. The study highlights the importance of careful normalization in RNA-seq data analysis, particularly in large collaborative projects involving multiple labs, technicians, and platforms.

Key Takeaways

RUV normalization effectively removes unwanted variation in RNA-seq data, leading to more accurate estimates of expression fold-changes and tests of differential expression.
The ERCC spike-in controls are not reliable enough to be used in standard global-scaling or regression-based normalization procedures due to their variable behavior across samples.
RUV is robust to the choice of control genes and can be applied to different datasets, including those with complex experimental designs and multiple sources of unwanted variation.

Causal analysis approaches in Ingenuity Pathway Analysis

This document presents causal analysis approaches implemented in Ingenuity Pathway Analysis (IPA) for interpreting gene-expression data. IPA uses a large-scale causal network derived from the Ingenuity Knowledge Base to infer upstream biological causes and downstream effects on cellular and organismal biology. The algorithms described include Upstream Regulator Analysis (URA), Mechanistic Networks (MN), Causal Network Analysis (CNA), and Downstream Effects Analysis (DEA). These tools enable scientists to combine directional information from gene-expression datasets with literature-derived knowledge to infer underlying causes of transcriptional changes and predict likely outcomes. The validity of the approach is demonstrated through example datasets, including analyses of beta-estradiol-treated MCF-7 cells and TNF-stimulated HUVEC cells. The tools have been used in various research applications, including characterizing mechanisms of breast cancer protection during pregnancy and understanding responses to the 2009 pandemic H1N1 influenza virus.

Key Takeaways

The causal analysis approaches in IPA provide a powerful means to interpret gene-expression data by leveraging prior biological knowledge and literature-curated causal relationships.
URA, MN, CNA, and DEA algorithms work together to identify upstream regulators, infer causal mechanisms, and predict downstream effects on biological functions and diseases.
The application of these tools to various datasets demonstrates their predictive power and utility in understanding complex biological systems and identifying potential therapeutic targets.

METHOD

DESeq2 is a method for differential analysis of count data from high-throughput sequencing assays, such as RNA-seq. It uses shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. The method models read counts using a negative binomial distribution and employs empirical Bayes shrinkage for dispersion and fold-change estimation. DESeq2 offers various features, including hypothesis tests for differential expression, automatic independent filtering, and a regularized logarithm transformation for quality assessment and clustering. The method is available as an R/Bioconductor package and has been benchmarked against other tools, showing high sensitivity and precision while controlling the false positive rate.

Key Takeaways

DESeq2 provides a comprehensive solution for gene-level analysis of RNA-seq data, incorporating shrinkage estimators to improve result stability and reproducibility.
The method's empirical Bayes priors enable automatic control of shrinkage based on available data information, making it suitable for both small and large studies.
DESeq2's shrinkage estimator for fold changes offers a statistically sound solution for comparing fold changes across the dynamic range of RNA-seq experiments, valuable for downstream analyses and prioritization of genes for follow-up studies.

ARTICLES

This study investigates the effects of enzymatic dissociation on gene expression in mouse and human brain tissue using single-cell sequencing. The authors demonstrate that enzymatic dissociation induces an aberrant ex vivo gene expression signature, particularly in microglia, which is prevalent in published literature and can confound downstream analyses. They present a validated protocol that preserves in vivo transcriptional profiles and cell-type diversity. The study also identifies a similar signature in postmortem human brain single-nucleus RNA-sequencing datasets and shows that it is induced by exposure to elevated temperatures ex vivo.

Key Takeaways

Enzymatic dissociation induces artifactual gene expression changes in microglia and other brain myeloid cells.
The use of transcriptional and translational inhibitors during dissociation can eliminate ex vivo activation.
A similar gene signature is present in postmortem human brain microglia and astrocytes, which can be induced by technical variation in sample processing.

HTSeq-a Python framework to work with high-throughput sequencing data

HTSeq is a Python library designed to facilitate the rapid development of scripts for processing and analyzing high-throughput sequencing (HTS) data. It provides parsers for common file formats, classes to represent genomic data, and tools for tasks such as read quality assessment and RNA-Seq data analysis. The library includes a core component, GenomicArray, which simplifies working with data associated with genomic coordinates. HTSeq also comes with extensive documentation and two stand-alone scripts, htseq-qa and htseq-count, for quality assessment and RNA-Seq data preprocessing, respectively. HTSeq aims to fill the gap between specialized tools and the need for customized code in HTS data analysis.

Key Takeaways

HTSeq provides a flexible framework for developing custom scripts for HTS data analysis, allowing users to handle diverse data types and formats.
The GenomicArray class is a key component of HTSeq, enabling efficient storage and retrieval of genomic-position-dependent data.
HTSeq's documentation and tutorial provide a comprehensive guide for users to develop their own scripts, including examples for common use cases such as aggregate coverage profiles and read counting.

STAR: ultrafast universal RNA-seq aligner

This document introduces STAR (Spliced Transcripts Alignment to a Reference), a novel RNA-seq alignment algorithm designed to accurately map high-throughput RNA-seq data to a reference genome. STAR outperforms existing aligners in terms of speed and accuracy, aligning 550 million 2x76 bp paired-end reads per hour on a 12-core server. The algorithm uses a sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching. STAR can detect canonical and non-canonical splice junctions, chimeric transcripts, and map full-length RNA sequences. Experimental validation of 1960 novel intergenic splice junctions showed an 80-90% success rate. STAR is implemented as a standalone C++ code and is available as open-source software under the GPLv3 license.

Key Takeaways

STAR significantly outperforms other RNA-seq aligners in mapping speed, achieving 550 million 2x76 bp paired-end reads per hour on a 12-core server.
The algorithm's high precision is corroborated by experimental validation of 1960 novel intergenic splice junctions with an 80-90% success rate.
STAR has the potential to serve as a universal alignment tool across emerging sequencing platforms due to its extensibility to long reads and compatibility with novel sequencing technologies.

ARTICLE

Metascape is a web-based portal designed to provide comprehensive gene list annotation and analysis for experimental biologists. It integrates over 40 knowledgebases to facilitate functional enrichment, interactome analysis, gene annotation, and membership search. The tool simplifies the analysis process through a one-click Express Analysis interface and provides interpretable outputs. Metascape enables comparative analyses across multiple independent experiments and is particularly useful for analyzing OMICs-based studies. The platform addresses the challenge of outdated databases in existing analysis portals by implementing a novel two-phase data synchronization approach, ensuring monthly updates. Key features include enrichment clustering to eliminate redundant terms, protein network analysis to identify complexes, and multi-gene-list meta-analysis to compare datasets. Metascape's architecture supports the analysis of an arbitrary number of gene lists and provides various visualizations, including enrichment bar graphs, networks, and heatmaps, to facilitate data interpretation.

Key Takeaways

Metascape offers a streamlined analysis workflow through its Express Analysis feature, making it accessible to experimental biologists without extensive computational training.
The platform's integration of over 40 knowledgebases and monthly data refresh cycles addresses the issue of outdated databases in existing tools.
Metascape's ability to perform meta-analysis on multiple gene lists simultaneously is a significant advancement over existing portals, which often lack this capability or provide limited support.
The tool's visualizations, such as enrichment networks and heatmaps, enhance the interpretability of complex OMICs data, facilitating the identification of common and selective pathways across datasets.
By providing a comprehensive and user-friendly analysis environment, Metascape has the potential to significantly enhance the biological interpretation of OMICs studies and aid in the discovery of novel therapeutic targets and mechanisms of action.

METHOD

This document introduces MAST, a statistical framework for analyzing single-cell RNA sequencing (scRNA-seq) data. It addresses challenges such as bimodal expression distributions and stochastic dropout by proposing a two-part generalized linear model. The model parameterizes both the rate of expression and the positive expression mean, allowing for the adjustment of the cellular detection rate (CDR) as a source of nuisance variation. MAST provides gene set enrichment analysis tailored to single-cell data and insights into how networks of co-expressed genes evolve across experimental treatments. The framework accommodates complex experimental designs and can estimate treatment effects while controlling for covariates, including technical factors. The authors illustrate MAST's application to two datasets: one comparing primary human non-stimulated and cytokine-activated mucosal-associated invariant T (MAIT) cells, and another studying temporal changes in murine bone marrow-derived dendritic cells subjected to lipopolysaccharide (LPS) stimulation. MAST identifies novel expression signatures of activation, highlights a population of MAIT cells showing partial activation, and recapitulates findings from the original publication on dendritic cells while describing additional coordinated gene expression changes.

Key Takeaways

MAST offers a statistically rigorous improvement over existing methods for scRNA-seq data analysis by adjusting for the cellular detection rate (CDR) and accommodating complex experimental designs.
The application of MAST to MAIT cells and dendritic cells datasets demonstrates its ability to identify novel expression signatures and characterize cellular heterogeneity.
MAST's gene set enrichment analysis and residual analysis capabilities provide deeper insights into the biological processes and co-expression networks involved in cellular responses to stimulation.

Molecular hallmarks of heterochronic parabiosis at single cell resolution

This study investigates the effects of heterochronic parabiosis on various cell types across 20 organs in mice, revealing cell type-specific responses to young or aged blood. The results show that certain cell types, such as adipose mesenchymal stromal cells, hematopoietic stem cells, and hepatocytes, are especially responsive to parabiosis. Young blood invokes novel gene sets in reverse to ageing patterns, and there is a global rescue of genes encoding electron transport chain subunits, pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. The study also observes an almost universal loss of gene expression with age that is largely mimicked by parabiosis.

Key Takeaways

Heterochronic parabiosis alters the transcriptomic landscape across cell types, with certain cell types being especially susceptible to gene expression changes.
Young blood reverses age-related gene expression changes and initiates novel pathways, including the rescue of genes encoding electron transport chain subunits.
The study reveals a complex interplay between blood-borne factors and cellular integrity, with implications for understanding ageing and rejuvenation.
The findings suggest possible avenues for therapeutic interventions, although further research is needed to explore the molecular and functional implications of the novel pathways identified.

DoubletFinder: Doublet Detection in Single-Cell RNA Sequencing Data Using Artificial Nearest Neighbors

This study presents DoubletFinder, a computational tool for detecting doublets in single-cell RNA sequencing (scRNA-seq) data using artificial nearest neighbors. DoubletFinder identifies doublets by simulating artificial doublets and comparing their gene expression profiles to real cells. The tool is benchmarked against ground-truth datasets and shown to outperform traditional methods like nUMI thresholding. DoubletFinder is particularly effective in detecting heterotypic doublets formed from transcriptionally distinct cells. The study also provides 'best practices' for applying DoubletFinder to real-world scRNA-seq data, including a method for estimating input parameters and accounting for homotypic doublets.

Key Takeaways

DoubletFinder accurately detects heterotypic doublets in scRNA-seq data, improving differential gene expression analysis.
The tool is insensitive to homotypic doublets and legitimate cell states with 'hybrid' expression profiles.
DoubletFinder can be used in conjunction with sample multiplexing techniques to enhance doublet detection and removal.
The method's performance is robust across different sequencing depths and datasets.
Users should carefully consider dataset diversity and adjust input parameters accordingly to optimize DoubletFinder's performance.

A human brain vascular atlas reveals diverse mediators of Alzheimer's risk

This study created a single-cell atlas of the human brain vasculature using Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) and profiled major human brain vascular and perivascular cell types through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 17 cognitively normal and Alzheimer's disease (AD) subjects. The study identified brain region- and species-enriched genes and pathways, revealed molecular principles of human arteriovenous organization, and discovered two subtypes of human pericytes. In AD, the study observed selective vulnerability of ECM-maintaining pericytes and gene expression patterns implicating dysregulated blood flow. The study also found that 30 of the top 45 AD GWAS genes are expressed in the human brain vasculature, confirmed by immunostaining.

Key Takeaways

The human brain vasculature plays a crucial role in brain health and disease, and its dysfunction contributes to various neurological disorders.
The study revealed a partial evolutionary transfer of AD risk genes and pathways from microglia to the vasculature from mice to humans.
The findings suggest an intertwined microglia-vascular axis expanded in humans, with vascular cells playing an auxiliary role via shared endocytosis and inflammatory pathways.
The study provides a comprehensive understanding of the diverse cell types contributing to AD risk and highlights the importance of considering vascular and perivascular cells in AD research.

ARTICLE

This study presents a novel droplet-based system for massively parallel digital transcriptional profiling of single cells, enabling the analysis of tens of thousands of cells. The system was validated using cell lines and synthetic RNAs, demonstrating high sensitivity and accuracy. The technology was applied to profile peripheral blood mononuclear cells and bone marrow mononuclear cells from transplant patients, revealing cellular heterogeneity and enabling the detection of rare cell populations and chimerism analysis.

Key Takeaways

The droplet-based system enables high-throughput single-cell RNA sequencing with rapid cell encapsulation and a high cell capture rate.
The technology was used to profile 68k peripheral blood mononuclear cells, revealing distinct immune populations and subpopulations.
A novel method was developed to infer cell origin in transplant bone marrow samples using single nucleotide variants identified from scRNA-seq data.

Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice

This study investigates the role of cis P-tau in vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). The authors found robust cis P-tau in patients with VaD and BCAS mice, and eliminating cis P-tau using cis mAb rescued VCID-like pathology and brain dysfunction. Pin1 was inhibited in VCID, and its overexpression or DAPK1 KO prevented VCID-like pathology. Cis mAb also prevented and ameliorated AD-like neurodegeneration and memory loss in htau mice. Single-cell RNA sequencing revealed diverse cortical cell type-specific transcriptomic changes in BCAS mice, which were largely recovered by cis mAb. Purified cis P-tau induced progressive neurodegeneration and brain dysfunction, and the cistauosis transcriptomic signature was shared in cis P-tau-injected and BCAS mice, as well as in human AD with early pathology.

Key Takeaways

Cis P-tau is a key driver of VCID and AD pathology.
Eliminating cis P-tau using cis mAb is a promising therapeutic approach.
Pin1 inhibition contributes to cis P-tau induction in VCID.
Cis mAb treatment restores transcriptomic changes in VCID mice.
Cis P-tau induces conserved transcriptomic changes relevant to cistauosis and axonopathy.

Single-cell transcriptomics of the developing lateral geniculate nucleus reveals insights into circuit assembly and refinement

This study employed single-cell RNA sequencing to develop a detailed transcriptome resource of gene expression across four time points in the developing dorsal lateral geniculate nucleus (LGN), a visual structure in the brain that undergoes postnatal circuit development. The analysis identified markers defining major LGN cell types, including excitatory relay neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells. Most cell types exhibited significant transcriptional changes across development, dynamically expressing genes involved in distinct processes including retinotopic mapping, synaptogenesis, myelination, and synaptic refinement. The data suggest that genes associated with synapse and circuit development are expressed in a larger proportion of nonneuronal cell types than previously appreciated. The study also used this single-cell expression atlas to identify the Prkcd-Cre mouse line as a tool for selective manipulation of relay neurons during late-stage sensory-driven synaptic refinement.

Key Takeaways

The study provides a comprehensive transcriptomic resource for understanding circuit assembly and refinement in the developing LGN.
Multiple cell types in the LGN, including nonneuronal cells, dynamically regulate gene expression during postnatal development, contributing to circuit development.
The Prkcd-Cre mouse line is identified as a valuable tool for manipulating relay neurons during late postnatal development, enabling further study of experience-dependent synaptic refinement.

Alzheimer's Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta

This study investigates the role of CD33 in Alzheimer's disease (AD) pathology, focusing on its expression in microglial cells and its impact on amyloid beta (Aβ) clearance. The research reveals that CD33 expression is increased in AD brains and is associated with reduced Aβ clearance. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, is linked to decreased CD33 expression and reduced insoluble Aβ42 levels. In vitro and in vivo experiments demonstrate that CD33 inhibits microglial uptake of Aβ42, and its inactivation or deletion leads to enhanced Aβ clearance and reduced amyloid plaque burden. The findings suggest that CD33 inhibition could be a novel therapeutic strategy for AD.

Key Takeaways

CD33 expression is increased in AD brains and is associated with reduced Aβ clearance.
The protective minor allele of rs3865444 is linked to decreased CD33 expression and reduced insoluble Aβ42 levels.
CD33 inhibits microglial uptake of Aβ42, and its inactivation enhances Aβ clearance.
CD33 deletion in APP/PS1 mice reduces amyloid plaque burden, indicating a potential therapeutic target for AD.

Religious Orders Study and Rush Memory and Aging Project

The Religious Orders Study and Rush Memory and Aging Project are ongoing longitudinal clinical-pathologic cohort studies of aging and Alzheimer's disease (AD). The studies have generated a wealth of data across a range of age-related phenotypes from the same individuals, including cognitive, motor, and decision-making abilities. Findings illustrate that cognitive decline as part of the AD dementia syndrome begins years or decades prior to AD dementia onset and MCI onset. The studies have also documented 9 pathologies on more than 1000 brains and found nearly 250 combinations, including AD pathology, TDP-43/hippocampal sclerosis, and several measures of macro- and micro-vascular disease. The data support the concept of a continuum of AD and highlight the complexity of the disease, with implications for drug discovery and treatment.

Key Takeaways

The studies demonstrate that cognitive decline begins years or decades prior to AD dementia onset, supporting a new framework for capturing the continuum of AD.
The presence of mixed pathologies, including AD pathology, TDP-43/hippocampal sclerosis, and cerebrovascular disease, is common in older adults and contributes to cognitive decline and dementia.
Neural reserve or resilience plays a crucial role in cognitive aging, with factors such as cognitive activity, purpose in life, and BDNF expression associated with more reserve.
The studies highlight the importance of considering non-cognitive phenotypes, such as motor function and decision making, in understanding the complex neurobiology of AD.
The findings have implications for drug discovery, suggesting that targeting resilience itself may be a promising therapeutic strategy.

APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia

This study investigates the relationship between lipid metabolism in microglia and Alzheimer's disease (AD) pathology, focusing on the APOE4/4 genotype. Single-nucleus RNA sequencing of AD brain tissue revealed a distinct microglial state characterized by the expression of ACSL1, a lipid droplet-associated enzyme. ACSL1+ microglia were most abundant in APOE4/4 patients. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induced ACSL1 expression, triglyceride synthesis, and lipid droplet accumulation in an APOE-dependent manner. Conditioned media from lipid droplet-containing microglia led to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. The findings suggest a link between genetic risk factors for AD and microglial lipid droplet accumulation, potentially providing therapeutic strategies for AD.

Key Takeaways

The APOE4/4 genotype is associated with increased lipid droplet accumulation in microglia, contributing to AD pathology.
ACSL1 is a key regulator of lipid droplet biogenesis in microglia and may serve as a functional protein marker of human lipid-droplet-accumulating microglia (LDAM).
PI3K inhibition reduces lipid droplet formation in microglia and reverses associated neurotoxicity, suggesting a potential therapeutic strategy for AD.

BRIEF COMMUNICATION

This study re-evaluated participants from a previous randomized controlled trial of lithium for amnestic mild cognitive impairment (MCI) after 11-15 years. The results showed that the lithium group had better long-term global cognitive outcomes than the placebo group, with significant differences in Mini Mental State Examination and phonemic Verbal Fluency Test scores. The study suggests that lithium treatment may be associated with long-term neuroprotective effects and potentially modify the disease progression in the MCI-AD continuum.

Key Takeaways

Lithium treatment was associated with better long-term cognitive outcomes in older adults with amnestic MCI.
The study provides evidence for the potential disease-modifying properties of lithium in the MCI-AD continuum.
The findings suggest that lithium may have a neuroprotective effect, potentially reducing the risk of dementia in older adults with MCI.

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo

This study investigates the effect of lithium chloride (LiCl), a glycogen synthase kinase-3 (GSK-3) inhibitor, on tauopathy in transgenic mice overexpressing mutant human tau. LiCl treatment significantly reduced GSK-3 activity and tau phosphorylation at specific epitopes. It also decreased levels of aggregated, insoluble tau in the brainstem and cortex. Administration of a second GSK-3 inhibitor, AR-A014418, confirmed these results. The reduction in insoluble tau correlated with decreased axonal degeneration when treatment was started early in the degenerative process. The findings suggest that GSK-3 inhibitors may be therapeutically beneficial for treating tauopathies, such as frontotemporal dementia and Alzheimer's disease.

Key Takeaways

Inhibiting GSK-3 with LiCl reduces tau phosphorylation and aggregation in transgenic mice.
Reduced insoluble tau levels correlate with decreased axonal degeneration when treatment is initiated early.
GSK-3 inhibitors may have therapeutic potential for treating tauopathies and Alzheimer's disease.

Lithium Reduces Tau Phosphorylation but Not A 𝛃 or Working Memory Deficits in a Transgenic Model with Both Plaques and Tangles

This study investigates the therapeutic efficacy of lithium in treating Alzheimer's disease (AD) using 3xTg-AD mice that develop both amyloid plaques and neurofibrillary tangles. Lithium administration reduced tau phosphorylation at specific sites but did not alter amyloid-beta (Aβ) load or improve working memory deficits. The reduction in tau phosphorylation was attributed to the inhibition of glycogen synthase kinase 3 (GSK-3) activity. The findings suggest that lithium may be beneficial in treating tauopathies and that combining it with other Aβ-mediated therapies could be advantageous for AD treatment.

Key Takeaways

Lithium reduces tau phosphorylation but not Aβ load in 3xTg-AD mice.
The reduction in tau phosphorylation is due to the inhibition of GSKG-3 activity.
Lithium does not improve working memory deficits in 3xTg-AD mice.
Combining lithium with other Aβ-mediated therapies may be beneficial for AD treatment.

Lithium suppresses A β pathology by inhibiting translation in an adult Drosophila model of Alzheimer's disease

This study investigates lithium's mechanism in reducing A β 42 protein levels and toxicity in an adult-onset Drosophila model of Alzheimer's disease. Lithium was found to decrease A β 42 levels by inhibiting protein synthesis, not degradation. It reduced overall translation, affecting proteins like GFP, and down-regulated translation initiation factors. Lithium also extended lifespan in A β -expressing flies and fission yeast, suggesting a conserved effect on longevity. The findings highlight lithium's potential therapeutic benefits in Alzheimer's disease and other neurodegenerative disorders.

Key Takeaways

Lithium reduces A β 42 levels by inhibiting protein synthesis, providing a potential therapeutic target for Alzheimer's disease.
The study demonstrates a conserved effect of lithium on longevity across species, including Drosophila and fission yeast.
Lithium's ability to down-regulate translation could be beneficial in various neurodegenerative disorders beyond Alzheimer's disease.

Neuroprotective Effects of Regulators of the Glycogen Synthase Kinase-3 𝛃 Signaling Pathway in a Transgenic Model of Alzheimer's Disease Are Associated with Reduced Amyloid Precursor Protein Phosphorylation

This study investigates the neuroprotective effects of inhibiting glycogen synthase kinase-3β (GSK3β) in a transgenic mouse model of Alzheimer's disease (AD). The researchers used lithium chloride treatment and genetic manipulation to block GSK3β activity, resulting in improved behavioral performance and reduced neurodegenerative alterations. The study found that GSK3β inhibition decreased amyloid-β production and tau phosphorylation by reducing amyloid precursor protein (APP) phosphorylation and maturation. The findings suggest that GSK3β is a potential therapeutic target for AD treatment.

Key Takeaways

Inhibiting GSK3β activity using lithium or genetic manipulation improves behavioral performance and reduces neurodegenerative alterations in a transgenic mouse model of AD.
GSK3β inhibition decreases amyloid-β production and tau phosphorylation by reducing APP phosphorylation and maturation.
The study provides evidence that GSK3β is a potential therapeutic target for AD treatment, supporting the use of GSK3β blockers as a promising new approach.

Lithium Improves Hippocampal Neurogenesis, Neuropathology and Cognitive Functions in APP Mutant Mice

This study examines the effects of lithium treatment on hippocampal neurogenesis, neuropathology, and cognitive functions in APP mutant mice modeling Alzheimer's disease. Lithium treatment stimulated hippocampal neurogenesis, improved cognitive functions, and reduced amyloid-β deposition in young TgCRND8 mice. The treatment activated the Wnt/β-catenin signalling pathway by inhibiting GSK-3β. However, lithium's effectiveness declined with age and increasing amyloid-β pathology. The findings suggest lithium may be beneficial in early stages of Alzheimer's disease by promoting neurogenesis and reducing amyloid-β burden.

Key Takeaways

Lithium treatment enhances hippocampal neurogenesis and cognitive functions in young APP mutant mice by activating Wnt/β-catenin signalling through GSK-3β inhibition.
The effectiveness of lithium treatment in stimulating neurogenesis and improving cognitive functions is age-dependent and declines with increasing amyloid-β deposition.
Lithium reduces amyloid-β burden and associated gliosis, potentially contributing to its neurogenic and cognitive benefits in early Alzheimer's disease models.

RESEARCH

This study investigates the effect of chronic lithium treatment on Alzheimer's disease (AD) pathology in PS1M146LxAPPSwe-London mice. The results show that lithium treatment reduces Abeta plaque toxicity by increasing plaque compaction and reducing the oligomeric halo, leading to decreased neuronal loss and axonal dystrophies. Lithium also promotes astrocyte activation and the release of heat shock proteins, which concentrate in the core of Abeta plaques. The study suggests that lithium may be a potential therapeutic intervention for AD by modifying Abeta plaque quality.

Key Takeaways

Lithium treatment reduces Abeta plaque toxicity by increasing plaque compaction and reducing the oligomeric halo.
Lithium promotes astrocyte activation and the release of heat shock proteins, which contribute to reduced plaque toxicity.
Early lithium intervention prevents neuronal loss in hippocampus and entorhinal cortex, and reduces axonal dystrophic pathology.

Beneficial synergistic effects of microdose lithium with pyrroloquinoline quinone in an Alzheimer's disease mouse model - ScienceDirect

This study investigates the beneficial effects of a novel compound, Li3PQQ, combining microdose lithium and pyrroloquinoline quinone (PQQ) in an Alzheimer's disease (AD) mouse model. The results show that Li3PQQ significantly improves cognitive function, reduces amyloid-β deposition and tau phosphorylation, and enhances synaptic plasticity in APP/PS1 transgenic mice. The mechanisms underlying these effects involve inhibition of GSK3α/β activities and increased ABAD activity. The study suggests that Li3PQQ may offer a promising therapeutic strategy for AD treatment with potentially lower lithium toxicity.

Key Takeaways

Li3PQQ improves cognitive function and reduces amyloid-β deposition and tau phosphorylation in APP/PS1 transgenic mice.
The compound's effects are associated with GSK3α/β inhibition and increased ABAD activity, suggesting a multifaceted therapeutic mechanism.
Li3PQQ may offer a safer alternative to traditional lithium treatment due to its lower accumulative effect and potential for better tolerance.

OPENACCESS

This study investigates the preventive and therapeutic effects of chronic microdose lithium treatment on Alzheimer's disease (AD) in a transgenic mouse model. The results show that lithium treatment prevented memory loss and neurohistopathological changes associated with AD. The treatment reduced anxiety-like behavior, preserved spatial and aversive-related memory, and protected against neuronal loss in the hippocampus and prefrontal cortex. Lithium also increased brain-derived neurotrophic factor (BDNF) density in the cortex and reduced the number of amyloid plaques. The study suggests that microdose lithium treatment may be a safe and effective preventive pharmacological therapy for AD.

Key Takeaways

Microdose lithium treatment prevents memory loss and neurohistopathological changes in a transgenic mouse model of Alzheimer's disease.
Lithium treatment reduces anxiety-like behavior and preserves spatial and aversive-related memory.
The treatment protects against neuronal loss in the hippocampus and prefrontal cortex, and increases BDNF density in the cortex.
Lithium reduces the number of amyloid plaques, a hallmark of Alzheimer's disease pathology.
The study suggests that microdose lithium may be a safe and effective preventive therapy for Alzheimer's disease.

Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3

This study investigates the role of glycogen synthase kinase 3 (GSK3) in regulating Toll-like receptor (TLR)-mediated cytokine production. The researchers found that GSK3 differentially regulates the production of pro- and anti-inflammatory cytokines in response to TLR stimulation. Inhibition of GSK3 resulted in increased production of the anti-inflammatory cytokine IL-10, while suppressing the production of proinflammatory cytokines such as IL-1β, IL-6, TNF, IL-12, and IFNγ. The study demonstrates that GSK3 regulates the inflammatory response by affecting the association of transcription factors NFκB p65 and CREB with the coactivator CBP. The findings suggest that GSK3 could be a potential therapeutic target for modulating the inflammatory response in conditions such as sepsis.

Key Takeaways

GSK3 inhibition differentially regulates pro- and anti-inflammatory cytokine production after TLR stimulation.
The mechanism involves differential regulation of NFκB p65 and CREB association with CBP.
GSK3 inhibition protects mice from endotoxin shock by reducing proinflammatory cytokines and increasing IL-10.
Targeting GSK3 may be a potential therapeutic strategy for inflammatory diseases like sepsis.

Deficiency in LRP6-mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer's Disease

This study investigates the role of LRP6-mediated Wnt signaling in Alzheimer's disease (AD) pathogenesis. The research demonstrates that neuronal LRP6 is critical for maintaining synaptic function and cognition. Conditional deletion of Lrp6 in mouse forebrain neurons leads to age-dependent deficits in synaptic integrity and memory. LRP6 deficiency in an amyloid mouse model exacerbates amyloid pathology due to increased APP processing to amyloid-β. In humans, LRP6 and Wnt signaling are significantly down-regulated in AD brains, likely by a mechanism that depends on amyloid-β. The findings suggest that restoring LRP6-mediated Wnt signaling could be a novel strategy for AD therapy.

Key Takeaways

LRP6-mediated Wnt signaling is essential for maintaining synaptic integrity and cognitive function.
Deficiency in LRP6-mediated Wnt signaling contributes to Alzheimer's disease pathogenesis by increasing amyloid pathology.
A vicious cycle between decreased LRP6-mediated Wnt signaling and increased amyloid-β levels promotes synaptic dysfunction and neurodegeneration in AD.
Restoring LRP6-mediated Wnt signaling may be a promising therapeutic strategy for Alzheimer's disease.

Inhibition of GSK-3 Ameliorates A b Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease

This study investigates the role of GSK-3 in Alzheimer's disease (AD) pathology using an adult-onset Drosophila model expressing Arctic mutant Aβ42 peptide. The model exhibits increased mortality, neuronal dysfunction, and behavioral impairments without neuronal loss. GSK-3 activity is increased in Aβ42-expressing flies, and inhibition of GSK-3 (genetically or pharmacologically) rescues Aβ42 toxicity. Loss of tau reduces Aβ42 toxicity, but GSK-3 inhibition has a greater protective effect, suggesting tau-independent mechanisms. GSK-3 inhibition reduces Aβ42 levels without affecting RNA transcript levels, implying a role in Aβ metabolism or clearance. The study supports the therapeutic potential of GSK-3 inhibitors in treating AD.

Key Takeaways

GSK-3 inhibition rescues Aβ42 toxicity in adult Drosophila
Loss of tau reduces Aβ42 toxicity, but GSK-3 inhibition has a greater protective effect
GSK-3 inhibition reduces Aβ42 levels without affecting RNA transcript levels
The study supports the therapeutic potential of GSK-3 inhibitors in treating Alzheimer's disease
The Drosophila model is suitable for studying AD pathology and testing therapeutic targets

A molecular mechanism for the effect of lithium on development

This study investigates lithium's mechanism of action in development and its potential therapeutic effects in bipolar disorder. The authors demonstrate that lithium inhibits glycogen synthase kinase-3β (GSK-3β), a key regulator of cell fate determination, and propose this as the primary mechanism for lithium's effects on development and potentially its therapeutic action in bipolar disorder. They show that complete inhibition of inositol monophosphatase (IMPase), a previously suggested target of lithium, has no effect on Xenopus development, ruling out IMPase as the primary target. Lithium's inhibition of GSK-3β is specific, potent, and uncompetitive, with a Ki of 2 mM. The study provides evidence that lithium's effects on development and glycogen metabolism are mediated through GSK-3β inhibition, and suggests that this pathway may be relevant to lithium's therapeutic effects in bipolar disorder.

Key Takeaways

Lithium's primary mechanism of action is through inhibition of GSK-3β, not IMPase.
GSK-3β inhibition by lithium is specific, potent, and uncompetitive.
Lithium's effects on development and glycogen metabolism are likely mediated through GSK-3β inhibition.
The study suggests a potential link between GSK-3β inhibition and lithium's therapeutic effects in bipolar disorder.

HHS Public Access

This review discusses the role of neuroinflammation in Alzheimer's disease (AD) pathogenesis, focusing on the interactions between immunological mechanisms and the neuronal compartment. Misfolded proteins bind to pattern recognition receptors on microglia and astroglia, triggering an innate immune response characterized by the release of inflammatory mediators. Genome-wide analysis suggests that several genes regulating glial clearance of misfolded proteins and the inflammatory reaction increase the risk for sporadic AD. External factors like systemic inflammation and obesity interfere with brain immunological processes, promoting disease progression. The review covers cellular players, including microglia and astrocytes, mediators and modulators of neuroinflammation, and the impact of systemic comorbidities on AD. It also discusses the detection of neuroinflammatory markers in CSF and blood, and the results of clinical trials using anti-inflammatory drugs and immunization therapies.

Key Takeaways

Neuroinflammation plays a significant role in Alzheimer's disease pathogenesis, with microglia and astrocytes contributing to the inflammatory response.
Modulation of microglial activation and inflammatory pathways may offer therapeutic strategies for AD, with potential targets including the NLRP3 inflammasome and nuclear receptors like PPARγ:RXR.
Systemic comorbidities like obesity and traumatic brain injury can exacerbate neuroinflammation and AD pathology, highlighting the importance of considering these factors in disease management.

Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer's disease

This study investigates the role of presynaptic proteins complexin-I and complexin-II in cognitive function across different stages of Alzheimer's disease (AD). Using a community-based sample of 418 deceased participants, the research found that complexin-I and complexin-II differentially influence cognitive function in early and late stages of AD. Complexin-I was strongly associated with cognitive function in early Braak stages (0-II), explaining 14.4% of the variance in global cognition, while complexin-II was associated with cognitive function in late Braak stages (V-VI), explaining 7.3% of the variance. The study suggests that disruption of inhibitory synaptic terminals may trigger early cognitive impairment, while excitatory terminal disruption contributes relatively more to later cognitive impairment. The findings support the hypothesis that complexin proteins are molecular components of brain reserve and have different functional roles according to the pathological stage of AD.

Key Takeaways

Complexin-I and complexin-II have distinct roles in cognitive function at different stages of Alzheimer's disease.
In early Braak stages (0-II), complexin-I is strongly associated with cognitive function, particularly in inhibitory synapses.
In late Braak stages (V-VI), complexin-II is associated with cognitive function, particularly in excitatory synapses.
The study provides evidence for the relevance of treatment strategies targeting inhibitory tone in early AD and excitatory function in late AD.
The findings have implications for understanding brain mechanisms of cognitive reserve and potential therapeutic interventions.

Glycogen synthase kinase-3 signaling in Alzheimer's disease

This review summarizes the current understanding of GSK3β neurobiology in Alzheimer's disease (AD), focusing on its effects on specific signaling pathways associated with AD pathophysiology. GSK3β is a key player in AD, influencing tau phosphorylation, amyloid-β production, memory, neurogenesis, and synaptic function. Dysregulation of GSK3β activity contributes to AD pathology, and its inhibition has been explored as a therapeutic strategy. The review discusses the feasibility of targeting GSK3β for AD treatment and provides an overview of current research efforts to develop GSK3β inhibitors in preclinical and clinical studies.

Key Takeaways

GSK3β is a critical kinase involved in multiple aspects of Alzheimer's disease pathology, including tau hyperphosphorylation, amyloid-β production, neuroinflammation, and synaptic dysfunction.
Inhibition of GSK3β activity has been shown to reduce AD-related pathology and improve cognitive function in animal models, making it a promising therapeutic target.
Despite promising preclinical results, clinical trials of GSK3β inhibitors have been limited by significant off-target effects and toxicological challenges.
Future research should focus on developing selective and organ-specific GSK3β inhibitors to overcome these challenges and realize the therapeutic potential of GSK3β modulation in AD.

REGULAR PAPER

This study investigates the immunocytochemical localization of glycogen synthase kinase-3 (GSK-3) in Alzheimer's disease (AD). The results show that GSK-3 α and GSK-3 β are strongly associated with granulovacuolar degeneration (GVD) in AD brains. GVD is a characteristic neuronal lesion in AD, and the study found that neurons exhibiting GSK-3-immunoreactive granules were more frequent in AD cases than in control subjects. The GSK-3 immunoreactivity was specific to the central dense granule of GVD and was observed with several different GSK-3 antibodies. The study also found that GVD exhibits immunoreactivity for phosphorylated tau, particularly at Ser262 and Thr212/Ser214, which are phosphorylation sites generated by GSK-3. The results suggest that active GSK-3 is sequestered into GVD and may contribute to the generation of phosphorylated tau epitopes in this localization. The study concludes that increased GSK-3 immunoreactivity in a subset of neurons is an additional molecular marker that quantitatively differentiates normal aging from AD.

Key Takeaways

The active form of GSK-3 is associated with granulovacuolar degeneration in Alzheimer's disease, suggesting a potential role in the disease pathology.
The sequestration of GSK-3 into GVD may represent a protective mechanism against cell death pathways.
The co-localization of GSK-3 with phosphorylated tau in GVD supports the hypothesis that GSK-3 contributes to tau phosphorylation in this context.

REFERENCES AND NOTES

The study investigates the role of zinc in Alzheimer's disease (AD) amyloid formation. It is shown that zinc concentrations above 300 nM rapidly destabilize human AP1-40 solutions, inducing tinctorial amyloid formation. Rat AP1-40, which binds zinc less avidly, is immune to these effects. The data suggest a role for cerebral zinc metabolism in the neuropathogenesis of AD. The cortical vasculature and hippocampus, areas severely affected in AD, contain high concentrations of zinc. Abnormalities in zinc metabolism, including decreased temporal lobe zinc concentrations and elevated CSF concentrations, have been reported in AD brains. The study establishes an assay system for studying AD amyloidosis and implies that zinc supplementation may be detrimental in AD subjects.

Key Takeaways

Zinc induces rapid amyloid formation of human AP1-40 at physiological concentrations, which may contribute to Alzheimer's disease neuropathogenesis.
The difference in zinc binding affinity between human and rat AP1-40 peptides explains their varying propensities for amyloid formation.
Abnormal cerebral zinc metabolism may play a crucial role in Alzheimer's disease pathology, particularly in regions with high zinc concentrations.
Zinc supplementation may be harmful in Alzheimer's disease subjects, potentially exacerbating cognitive decline.

Gene sets

This document analyzes the statistical properties of gene-set analysis (GSA), a method used to understand the biological implications of genome-wide association studies (GWAS). GSA aggregates genetic variants to genes and then to gene sets based on shared biological properties. The document evaluates the core structure of GSA, examines current implementations, and shows factors affecting valid detection of gene sets. It discusses self-contained and competitive GSA, gene-association measures, and confounding factors such as overall heritability, biological and methodological confounding, and linkage disequilibrium. The analysis includes simulations to assess the statistical behavior of GSA and its power to detect gene sets. The results show that self-contained GSA is sensitive to overall heritability, while competitive GSA is more robust. The document also discusses the implications of the findings for interpreting GSA results and highlights the need for sound GSA tools with known statistical properties.

Key Takeaways

Self-contained GSA is limited by its inability to account for overall heritability, making it less informative for polygenic phenotypes.
Competitive GSA effectively addresses the issue of overall heritability but is vulnerable to biases from gene size, density, and linkage disequilibrium.
The power of competitive GSA decreases as the heritability of the phenotype increases and improves only limitedly with sample size.
GSA can be viewed as part of a broader framework called generalized gene-level analysis, which encompasses various types of gene-level analyses.
The statistical behavior of GSA is expected to carry over to other types of gene-level analysis, emphasizing the need for robust statistical methods.

ARTICLE IN PRESS

This study analyzed alkali metals (Na, K, Li, Rb, and Cs) levels in 14 different brain regions of 42 non-diseased individuals using various analytical techniques. Potassium was found to be the most abundant alkali metal, followed by Na, Rb, Cs, and Li. The distribution of Li, K, and Cs was heterogeneous, while Rb and Na were more homogeneously distributed. Age-related changes were observed in Na and Rb levels in specific brain regions, such as the hippocampus. The study provides comprehensive data on alkali metals levels in non-diseased human brain, contributing to defining 'normal' levels for future comparisons with data from patients affected by neurodegenerative diseases.

Key Takeaways

The heterogeneous distribution of alkali metals across the human brain highlights the importance of defining specific brain regions when studying elemental composition in neurodegenerative diseases.
Age-related changes in Na and Rb levels were observed in specific brain regions, such as the hippocampus, suggesting potential implications for neurodegenerative processes.
Higher levels of K, Rb, and Cs were found in the brain of smokers compared to non-smokers, potentially due to decreased activity and/or expression of Na+/K+-ATPase.

Metallomics

This review discusses the complex interactions between neurometals and amyloidogenic proteins at the synapse and their role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, prion diseases, Lewy body diseases, and vascular dementia. The authors propose a hypothesis that the disruption of metal homeostasis contributes to the conformational changes of amyloidogenic proteins and the development of these diseases. They discuss the characteristics of neurometals, including iron, zinc, copper, and manganese, and their roles in normal brain function. The review also examines the interactions between metals and amyloidogenic proteins, such as amyloid-β protein, prion protein, and α-synuclein, and their implications in disease pathogenesis. The authors suggest that the cross talk between metals and amyloidogenic proteins at the synapse is essential for normal brain function and that its disruption may contribute to neurodegenerative diseases.

Key Takeaways

The disruption of metal homeostasis is a common mechanism underlying the pathogenesis of neurodegenerative diseases.
The interactions between metals and amyloidogenic proteins at the synapse play a crucial role in maintaining normal brain function and synaptic plasticity.
The conformational changes of amyloidogenic proteins, such as amyloid-β protein and prion protein, are influenced by metal binding and contribute to neurotoxicity.
Carnosine, an endogenous antioxidant and anti-cross-linking peptide, may have neuroprotective functions in the brain and potentially be used as a treatment for neurodegenerative diseases.
Further research on neurometallomics is necessary to understand the molecular mechanisms of synaptic degeneration and the quantitative analysis of neurometals in neurodegenerative diseases.

Increased level of active GSK-3 b in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration

This study investigates the role of glycogen synthase kinase-3β (GSK-3β) in Alzheimer's disease (AD) and its relationship with tau phosphorylation and aggregation. The authors found increased levels of active GSK-3β in AD brains and observed its accumulation in neurones at different stages of neurofibrillary degeneration. GSK-3β colocalized with phosphotau epitopes in the somatodendritic compartment, suggesting its involvement in tau hyperphosphorylation. The study also found GSK-3β association with argyrophilic grains in argyrophilic grain disease but not with Lewy bodies in diffuse Lewy body disease.

Key Takeaways

Active GSK-3β accumulation is an early event in neurofibrillary degeneration and accompanies NFT formation.
GSK-3β is associated with tau-positive inclusions in different tauopathies, including AD and argyrophilic grain disease.
The study suggests GSK-3β plays a crucial role in tau hyperphosphorylation and neuronal dysfunction in AD.

GSK3 b Negatively Regulates Oligodendrocyte Differentiation and Myelination In Vivo

This study examines the role of GSK3 b in oligodendrocyte differentiation and myelination in vivo and ex vivo. GSK3 b inhibitors were administered into the lateral ventricle of postnatal mice, and the effects on oligodendrocyte precursors (OPs) and oligodendrocytes (OLs) were analyzed. The results show that GSK3 b inhibition increases OPs and OLs and promotes myelination. GSK3 b inhibition stimulates OP proliferation and is prosurvival and antiapoptotic. The effects of GSK3 b inhibition on OPs are via the canonical Wnt signaling pathway, but GSK3 b inhibition and Wnt3a have opposing actions on OL differentiation. GSK3 b inhibition overrides the negative effects of Wnt3a on OLs and stimulates OL differentiation via multiple mechanisms, including CREB and Notch1 signaling. In the adult, GSK3 b inhibition stimulates OL regeneration and remyelination following demyelination.

Key Takeaways

GSK3 b is a negative regulator of oligodendrocyte differentiation and myelination.
Inhibiting GSK3 b promotes oligodendrocyte regeneration and remyelination in demyelinating lesions.
GSK3 b inhibition overrides the negative effects of Wnt3a signaling on oligodendrocyte differentiation.
The study highlights the potential of targeting GSK3 b as a therapeutic approach for promoting oligodendrocyte regeneration and remyelination in demyelinating diseases.

Quantitative Measurement of [Na+] and [K+] in Postmortem Human Brain Tissue Indicates Disturbances in Subjects with Alzheimer's Disease and Dementia with Lewy Bodies

This study measured Na+ and K+ concentrations in postmortem human brain tissue from patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and age-matched controls using ICP-MS. The results showed that [Na+] was significantly higher in severe AD brains compared to controls, correlating positively with Braak stage. [K+] was lower in moderate AD but not significantly different in severe AD or DLB. A positive correlation was found between [K+] and Aβ plaque load, as well as frontal tissue pH. The findings suggest disturbances in brain Na+ and K+ homeostasis in AD, potentially related to disease severity and pathology.

Key Takeaways

The study demonstrates a significant elevation in [Na+] in severe AD brains, correlating with disease severity as measured by Braak stage.
Changes in [K+] were observed in moderate AD, but not in severe AD or DLB, suggesting a complex relationship between K+ homeostasis and AD pathology.
The positive correlation between [K+] and Aβ plaque load suggests a potential link between K+ channel dysfunction and Aβ accumulation in AD.

A feasibility and tolerability study of lithium in Alzheimer's disease

This study assessed the safety and feasibility of long-term lithium treatment in elderly patients with mild to moderate Alzheimer's disease (AD). Twenty-two patients initiated lithium therapy, with 14 discontinuing after a mean of 16 weeks. Three patients discontinued due to possible side effects that resolved upon cessation. The study found that lithium treatment had relatively few side effects, which were mild and reversible. However, discontinuation rates were high, and the presence of contraindications to lithium in the elderly AD population was significant. The study suggests that while lithium can be safely prescribed to some patients with late-onset AD, its potential use is limited by contraindications, discontinuation, and risk of serious toxicity.

Key Takeaways

Lithium treatment in elderly AD patients is feasible but limited by high discontinuation rates and contraindications.
The study highlights the need for careful patient selection and monitoring when considering lithium therapy for AD.
Further research is required to determine the efficacy of lithium as a disease-modifying therapy for AD.

Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry

This article discusses the target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. The authors clarify their preferred methodology by addressing four issues based on observed decoy hit frequencies: the major assumptions made with this database search strategy are reasonable, concatenated target-decoy database searches are preferable to separate target and decoy database searches, the theoretical error associated with target-decoy false positive rate measurements can be estimated, and alternate methods for constructing decoy databases are similarly effective once certain considerations are taken into account. The target-decoy strategy involves creating a composite database by appending a decoy database to a target database, and then searching MS/MS spectra against this composite database. The number of decoy hits is used to estimate the number of false positive identifications, allowing researchers to derive other measurements that help evaluate and compare scoring methods and data sets.

Key Takeaways

The target-decoy search strategy provides a robust and effective way to estimate false positive identifications in large-scale proteomics data.
Concatenated target-decoy database searches are preferable to separate searches as they allow for direct competition between target and decoy sequences, reducing the overestimation of false positive rates.
The theoretical error associated with target-decoy false positive rate measurements can be estimated using equations derived from simulated data, allowing researchers to place confidence intervals on their estimates.
Alternate decoy database construction methods, such as protein reversal, peptide pseudo-reversal, random, and Markov chain models, can be similarly effective in estimating false positive identifications, once certain considerations are taken into account.

Dysregulated Wnt Signalling in the Alzheimer's Brain

This review examines the role of Wnt signalling in the central nervous system (CNS) and its dysregulation in Alzheimer's disease (AD). Wnt signalling regulates various cellular processes, including neurogenesis, synapse number and function, and blood brain barrier (BBB) biology. Dysregulated Wnt signalling has been implicated in AD pathogenesis, contributing to pathophysiological manifestations such as aberrant amyloid precursor protein (APP) processing, tau pathology, synapse loss, neuroinflammation, and BBB breakdown. The review discusses the connections between Wnt signalling and AD-related pathological processes, including the role of Wnt signalling in APP processing, tau hyperphosphorylation, synaptic dysfunction, microglial pathology, and BBB dysfunction. It also explores the potential for therapeutic intervention in AD via modulation of the Wnt signalling pathway.

Key Takeaways

Dysregulated Wnt signalling contributes to various AD pathologies, including APP processing, tau pathology, synapse loss, and neuroinflammation.
Restoring Wnt signalling may offer therapeutic opportunities for AD treatment, with potential targets including DKK1 and TREM2.
Further research is needed to understand the complex interactions between Wnt signalling and other pathways in AD, as well as the specific cellular and molecular mechanisms involved.

Free Radical Biology & Medicine

This study investigates the role of labile copper (Cu) in Alzheimer disease (AD) pathology. The authors measured Cu content in postmortem cortical tissue from nondemented elderly controls and AD cases using inductively coupled plasma mass spectroscopy and assessed labile Cu using the Cu-phenanthroline assay. They found elevated levels of exchangeable Cu2+ in AD cortical tissue, which correlated with tissue oxidative damage. The study also showed an increased capacity of AD cortical tissue samples to bind Cu2+. The findings suggest that deranged Cu homeostasis contributes to oxidative stress in AD and support biometal metabolism as a therapeutic target.

Key Takeaways

Elevated labile Cu is associated with oxidative pathology in Alzheimer disease.
Deranged Cu homeostasis in AD cortex is characterized by increased exchangeable Cu2+ and Cu2+-binding capacity.
The study's findings support targeting biometal metabolism as a therapeutic approach for AD.

Elevated cortical zinc in Alzheimer disease

This study investigates the relationship between brain biometals and Alzheimer disease (AD) pathology. The authors measured zinc, copper, iron, manganese, and aluminum levels in postmortem neocortical tissue from patients with AD, normal age-matched controls, and patients with schizophrenia. The results show a significant increase in zinc levels in AD-affected cortex, which correlates with amyloid-β peptide (Aβ) burden and dementia severity. The study suggests that zinc accumulation is a prominent feature of advanced AD and is biochemically linked to Aβ accumulation and dementia severity.

Key Takeaways

Zinc accumulation in the neocortex is a hallmark of advanced Alzheimer disease and correlates with Aβ burden and dementia severity.
The elevation of zinc in AD is not solely due to its accumulation within amyloid plaques, suggesting a more complex mechanism involving cellular zinc homeostasis.
The study's findings have implications for understanding the therapeutic mechanism of metal-complexing agents, such as clioquinol, which may redistribute metals away from areas of abnormal accumulation.

Article

This study conducted a meta-analysis of 56 studies to evaluate copper dysregulation as an Alzheimer's disease (AD) susceptibility factor. The analysis included brain specimens and serum/plasma samples from AD patients and healthy controls. Results showed decreased copper in AD brain specimens, increased copper and non-bound ceruloplasmin copper in serum/plasma samples, and unchanged ceruloplasmin levels. Serum/plasma copper excess was associated with a three to fourfold increase in AD risk. A replication study confirmed these findings and showed that carriers of the ATP7B AG haplotype were more frequent in AD patients. The study suggests that copper imbalance could be considered an AD susceptibility factor, particularly in a subset of patients who may benefit from precision medicine strategies.

Key Takeaways

Copper imbalance is associated with increased risk of Alzheimer's disease.
Non-ceruloplasmin copper is a potential biomarker for predicting AD progression.
ATP7B gene variants are linked to copper dysregulation and AD susceptibility.
Copper dyshomeostasis may be a target for precision medicine-based strategies in AD.
Lifestyle and dietary changes may help reduce AD risk associated with copper imbalance.

Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial

This randomized clinical trial investigated the effects of long-term lithium treatment on cognitive and functional decline in older adults with amnestic mild cognitive impairment (MCI). The study involved 61 participants who received either lithium or placebo for 2 years, followed by a single-blinded extension phase for an additional 24 months. The results showed that lithium-treated patients remained cognitively and functionally stable over 2 years, whereas the placebo group displayed significant decline. Lithium treatment was associated with better performance on memory and attention tests and a significant increase in cerebrospinal fluid amyloid-beta peptide after 36 months. The study suggests that long-term lithium treatment may attenuate cognitive and functional decline in amnestic MCI and modify Alzheimer's disease-related biomarkers.

Key Takeaways

Lithium treatment stabilizes cognitive and functional abilities in patients with amnestic MCI.
Long-term lithium use is associated with increased cerebrospinal fluid amyloid-beta peptide, suggesting potential disease-modifying effects.
The study's findings support the potential use of lithium as a therapeutic approach for Alzheimer's disease prevention or treatment.

Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial {

This study evaluated the effect of long-term lithium treatment on cognitive and biological outcomes in individuals with amnestic mild cognitive impairment (aMCI). Forty-five participants were randomized to receive lithium or placebo for 12 months. Lithium treatment was associated with a significant decrease in cerebrospinal fluid concentrations of phosphorylated tau (P-tau) and better performance on cognitive tests. The study suggests that lithium has disease-modifying properties with potential clinical implications in preventing Alzheimer's disease.

Key Takeaways

Lithium treatment reduced cognitive decline in individuals with aMCI compared to placebo.
The reduction in cerebrospinal fluid P-tau concentrations may be a useful parameter to predict the preventive effects of lithium on conversion from aMCI to Alzheimer's disease.
The disease-modifying effect of lithium may be stage-dependent, with individuals at earlier stages of the disease continuum benefiting most from treatment.

The document appears to be a copyright notice from the Nature Publishing Group, dated 1983. It indicates that the content is protected by copyright law, and the publishing group holds the rights to the material. The notice is likely included in publications or documents produced by the Nature Publishing Group during that year.

Key Takeaways

The document signifies the importance of copyright protection in academic and scientific publishing.
It highlights the role of the Nature Publishing Group as a major publisher of scientific research in 1983.
The presence of a copyright notice suggests that the content was considered valuable and worthy of legal protection.

Methods in Neuroepidemiology

This study examines the accuracy of clinical diagnosis of Alzheimer's disease (AD) in two community-based cohort studies (Religious Orders Study and Rush Memory and Aging Project) compared to a clinic-based cohort study. The clinical diagnosis was made using a computer-based system of prediction rules without informant interviews, neuroimaging, or routine case conferencing. The positive predictive value (PPV) of the clinical diagnosis was compared to the pathologic diagnosis of AD using CERAD neuropathologic criteria as the gold standard. The results show that the PPV of clinically probable AD was 92.2% in the community-based studies and 93.5% in the clinic-based study. The PPV of clinically possible AD was 70.3% in the community-based studies and 94.4% in the clinic-based study. The study suggests that the clinical diagnosis of AD can be made accurately in community-based studies using decision rules, which holds promise for reducing operational costs.

Key Takeaways

The clinical diagnosis of Alzheimer's disease can be made accurately in community-based studies using decision rules without informant interviews, neuroimaging, or routine case conferencing.
The positive predictive value of clinically probable AD was high in both community-based and clinic-based studies, indicating that the clinical diagnosis is reliable.
The presence of cerebral infarctions was more common in community-based studies and in cases with possible AD, suggesting that MRI may be useful in detecting cerebrovascular disease and potentially increasing the diagnosis of vascular dementia.

HHS Public Access

This study conducted a large genome-wide association meta-analysis of clinically diagnosed late-onset Alzheimer's disease (LOAD) in 94,437 individuals, identifying five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX) and confirming 20 previous LOAD risk loci. Pathway analysis implicated immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing genetic variants affecting APP and Aβ processing are associated with LOAD. Fine-mapping of the human leukocyte antigen (HLA) region confirmed the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. The study also identified genetic correlations between LOAD and traits such as family history of dementia and education.

Key Takeaways

The study identified new genetic risk loci for Alzheimer's disease, highlighting the importance of immunity and lipid processing in disease pathology.
Pathway analysis revealed that genetic variants affecting APP and Aβ processing are associated with LOAD, suggesting potential therapeutic targets.
Fine-mapping of the HLA region confirmed the DR15 haplotype as a risk factor for LOAD, pointing to a central role of immune-mediated mechanisms in disease risk.

Protocol

This document presents an optimized protocol for isolating microglia from mouse brain tissue using mechanical homogenization to preserve transcriptomic integrity. The protocol involves Dounce homogenization at 4°C to generate a single-cell suspension, followed by Percoll gradient centrifugation and flow cytometry to isolate microglia. The isolated microglia exhibit a gene expression pattern without changes induced by heated enzymatic digestion. The protocol is suitable for multiple sequencing endpoints and has been successfully applied to mice between the ages of P0 and 12 months. The authors discuss the limitations of the protocol, including reduced cell yield due to mechanical dissociation and potential issues with Ly6C expression in microglia at different ages or disease models. They also provide troubleshooting tips for common problems encountered during the protocol.

Key Takeaways

The protocol preserves transcriptomic integrity by avoiding enzymatic dissociation at 37°C, which can introduce drastic transcriptomic changes.
Mechanical homogenization results in reduced cell yield compared to enzymatic dissociation, but is necessary to maintain transcriptomic integrity.
The protocol is suitable for multiple sequencing endpoints, including RNA sequencing and single-cell RNA sequencing, but may require optimization for specific applications.

Heavy Metals Exposure and Alzheimer's Disease and Related Dementias

Alzheimer's disease and related dementias are major public health challenges with no effective treatment or cure. Exposure to heavy metals like lead, cadmium, and manganese is associated with increased risk of cognitive decline and Alzheimer's disease. These metals are widespread in the environment, can enter cells and reach the brain, and have been shown to cause neurotoxicity and AD-related pathology in animal models. Epidemiologic studies have consistently linked lead, cadmium, and manganese exposure to impaired cognitive function and cognitive decline in adults. However, more longitudinal studies are needed to confirm the association between these metals and Alzheimer's disease specifically.

Key Takeaways

Exposure to lead, cadmium, and manganese is ubiquitous and can cause neurotoxicity and AD-related pathology.
These metals are associated with impaired cognitive function and cognitive decline in adults.
More research is needed to understand the prospective association between heavy metal exposure and clinical Alzheimer's disease.
Reducing exposure to lead, cadmium, and manganese should be a public health priority to prevent Alzheimer's disease and related dementias.
The neurological effects of manganese exposure depend on levels of other essential metals.

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

This review examines the role of metal toxicity in Alzheimer's disease (AD) and neuroinflammation. The authors discuss how exposure to various metals, both essential and non-essential, can contribute to the onset and progression of AD. Essential metals like iron, copper, zinc, and manganese play crucial roles in brain physiology, but their dysregulation can lead to neurotoxicity. Non-essential metals such as lead, aluminum, and cadmium can also induce neurotoxicity and contribute to AD pathology. The review highlights the complex interactions between metals, amyloid-beta, tau protein, and neuroinflammation, and discusses potential therapeutic strategies targeting metal homeostasis.

Key Takeaways

Dysregulation of essential metals like iron, copper, and zinc contributes to Alzheimer's disease pathology by promoting amyloid-beta aggregation and tau hyperphosphorylation.
Non-essential metals such as lead, aluminum, and cadmium can induce neurotoxicity and contribute to Alzheimer's disease pathology.
Metal chelators have shown promise as therapeutic agents in Alzheimer's disease models by reducing metal-mediated toxicity and amyloid-beta accumulation.
The complex interactions between metals, amyloid-beta, tau protein, and neuroinflammation require further investigation to understand the underlying mechanisms and identify potential therapeutic targets.
Restoring metal homeostasis may be a potential strategy to treat or prevent Alzheimer's disease, but further research is needed to understand the optimal approaches and potential risks.

Insights into Alzheimer's disease from single cell genomic approaches

This document discusses how single cell genomic approaches have revealed cell-type specific molecular perturbations in Alzheimer's disease (AD). It highlights the complex interplay of various brain cell types in AD and how genomic information from single cells expands existing paradigms of AD pathogenesis. The document discusses the molecular disturbances across major cell types, including excitatory neurons, interneurons, microglia, astrocytes, oligodendrocytes, and vascular cells, and how these disturbances converge on common signaling pathways such as lipid handling, immune response, and metabolic reprogramming. The findings suggest that defining and manipulating core signaling nodes may generate new opportunities for therapeutic intervention.

Key Takeaways

Single cell genomics reveals cell-type specific alterations in AD, highlighting core signaling pathways that are dysfunctional across cell types.
The document identifies common perturbed pathways across multiple cell types in AD, including immune signaling, lipid handling, unfolded protein response, DNA damage, and vascular interactions.
The findings suggest that manipulating disrupted cellular states may pave the way for new therapeutic opportunities in AD treatment.

The Jackson Laboratory

Mouse Genome Informatics (MGI) is a comprehensive knowledgebase system that integrates information about the laboratory mouse, serving as a model system for understanding human biology and disease. MGI includes several core databases such as the Mouse Genome Database (MGD) and the Gene Expression Database (GXD), providing access to data on genome features, variation, expression, gene function, phenotype, and human disease models. The system utilizes controlled vocabularies and biological ontologies to standardize data annotation and facilitate integration. MGI offers various search tools, including Quick Search and specialized search forms, as well as interactive genome browsers like JBrowse and Multiple Genome Viewer. Recent enhancements include automated literature acquisition, renovation of the Quick Search tool, expanded representation of regulatory features, and new cell type annotations for expression data. MGI is a founding member of the Alliance of Genome Resources and contributes to the Gene Ontology Consortium.

Key Takeaways

MGI has automated its literature acquisition process, increasing the rate of relevant papers entered into the system and freeing curators to focus on data curation.
The Quick Search tool has been renovated to improve usability and performance, featuring separate tabs for different data types and filter options.
MGI has expanded its representation of regulatory features, including enhancers, CTCF binding sites, and promoters, with links to external resources.
GXD has introduced a new Expression Profile Search tool, allowing users to search for genes based on their expression profiles across multiple anatomical structures.
MGI continues to enhance its resources, including plans to integrate scRNA-Seq data, improve the Multiple Genome Viewer, and support the development of a reference mouse pangenome.

Integrated analysis of multimodal single-cell data

This document introduces a computational method called 'weighted nearest neighbor' (WNN) analysis for integrating multiple data types measured within the same cell. The authors apply WNN to a CITE-seq dataset of human peripheral blood mononuclear cells (PBMCs) to construct a multimodal reference atlas of the circulating immune system. The analysis substantially improves the ability to resolve cell states and identify previously unreported lymphoid subpopulations. The authors also demonstrate how to leverage this reference to rapidly map new datasets and interpret immune responses to vaccination and COVID-19.

Key Takeaways

WNN analysis is a robust and flexible approach for multimodal analysis, allowing for the integration of multiple data types and improving the characterization of cellular diversity.
The multimodal atlas of human PBMCs reveals extensive lymphoid heterogeneity, including the expression of integrin proteins on circulating memory T cells and a gradient of adaptive-like responses in NK cells.
The authors demonstrate the ability to map scRNA-seq data onto the multimodal reference, improving cell type identification and enabling the characterization of complex immune responses.

A Reliable Way to Detect Endogenous Murine b -Amyloid

This study investigates the background signal in ELISAs for murine β-amyloid and identifies reliable methods for detecting endogenous β-amyloid in rodent brain tissue. The authors examined several commercial ELISAs and found that most showed high background signal due to non-APP derived proteins. However, the Wako β-Amyloid 42 High-Sensitive kit and β-Amyloid 40 kit showed minimal background signal. The study used APP-KO mice to determine the source of background noise and found that it was primarily due to non-APP related proteins. The authors also designed a human-specific β-amyloid ELISA to further investigate the issue. They conclude that certain ELISAs can reliably detect endogenous murine β-amyloid without prior solid-phase extraction.

Key Takeaways

The Wako β-Amyloid 42 High-Sensitive kit is a reliable method for detecting endogenous murine β-amyloid with minimal background signal.
The majority of background signal in ELISAs for murine β-amyloid is due to non-APP derived proteins.
Different ELISAs vary significantly in their signal-to-noise ratio, with the Wako kits showing the best performance.
The choice of ELISA kit depends on the specific experimental design, including the need to distinguish between endogenous and human β-amyloid in transgenic mice.

Evidence for widespread, severe brain copper deficiency in Alzheimer's dementia

This study investigated metal concentrations in post-mortem brain tissue from Alzheimer's disease (AD) cases and controls. The research measured levels of eight essential metals and selenium in seven brain regions using inductively-coupled-plasma mass spectrometry. The findings revealed a significant decrease in copper levels across all seven brain regions in AD cases, consistent with pan-cerebral copper deficiency. Other metals showed region-specific changes, but copper deficiency was widespread. The study suggests that copper deficiency may contribute to AD pathogenesis and proposes that interventions aimed at safely elevating brain copper could provide a new therapeutic approach.

Key Takeaways

Copper levels were significantly decreased in all seven brain regions examined in AD cases, indicating pan-cerebral copper deficiency.
The observed copper deficiency may contribute to the pathogenesis of neurodegeneration and dementia in AD, potentially through defects in energy utilization and antioxidant defenses.
The study's findings support the potential for therapeutic interventions that safely restore brain copper levels, which could have beneficial effects in treating AD.
The copper deficiency observed in AD brains approximates levels seen in Menkes' disease, a disorder characterized by severe brain damage due to copper deficiency.
Further research is needed to develop effective methods for measuring and therapeutically raising brain copper levels in AD patients.

Review

Genome-wide association studies and functional genomics have linked specific cell types, genes, and pathways to Alzheimer's disease (AD) risk, implicating microglia in AD etiology. AD risk alleles primarily affect genes expressed in macrophages, converging on pathways like endocytosis/phagocytosis, cholesterol metabolism, and immune response, with critical roles in microglial efferocytosis. This review highlights relevant genes identified in recent AD genetics and genomics studies and describes their contribution to AD pathogenesis. Microglial efferocytosis is essential for maintaining tissue homeostasis and immune tolerance. Dysregulation of efferocytosis has been implicated in AD, with several AD risk genes (TREM2, APOE, PLCG2) playing critical roles in this process. The review discusses the functional interpretation of AD genetic architecture, focusing on the efferocytosis pathway and its potential as a therapeutic target.

Key Takeaways

Microglial efferocytosis is a critical process in maintaining brain homeostasis and is dysregulated in Alzheimer's disease.
Genetic variants associated with AD risk converge on pathways related to microglial efferocytosis, including recognition and engulfment, digestion, and adaptation.
TREM2 and APOE are key genes involved in microglial efferocytosis, with TREM2 R47H variant and APOE4 isoform contributing to impaired efferocytosis and increased AD risk.
Modulating microglial efferocytosis is a potential therapeutic strategy for AD, with targets including TREM2, MS4A4A/MS4A6A, CD33, PU.1, PLCG2, and INPP5D/SHIP1.
Further research is needed to understand the complex genetics of AD and the role of microglial efferocytosis in disease pathogenesis.

Association of Lithium in Drinking Water With the Incidence of Dementia | Dementia and Cognitive Impairment | JAMA Psychiatry | JAMA Network

This Danish nationwide study investigated the association between lithium levels in drinking water and dementia incidence. Analyzing data from 73,731 patients with dementia and 733,653 controls, the study found a nonlinear association between lithium exposure and dementia incidence. Higher lithium levels (>15.0 µg/L) were associated with a lower incidence of dementia (IRR, 0.83; 95% CI, 0.81-0.85; P < .001). Similar patterns were observed for Alzheimer disease and vascular dementia. The study suggests that long-term exposure to higher lithium levels in drinking water may be associated with a lower incidence of dementia.

Key Takeaways

The study found a nonlinear association between lithium exposure in drinking water and dementia incidence, with higher levels (>15.0 µg/L) associated with lower dementia incidence.
The association was consistent across dementia subtypes, including Alzheimer disease and vascular dementia.
The findings suggest that long-term exposure to microlevels of lithium may have neuroprotective effects, potentially modifying the risk of developing dementia.

Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons | Geriatrics | JAMA Psychiatry | JAMA Network

This study investigated cortical proteins associated with cognitive resilience in community-dwelling older persons. Using data from 391 participants in the Religious Orders Study and Rush Memory and Aging Project, the researchers conducted a proteome-wide association analysis of the human dorsolateral prefrontal cortex. They identified eight cortical proteins associated with cognitive resilience: NRN1, ACTN4, EPHX4, RPH3A, SGTB, CPLX1, SH3GL1, and UBA1. Higher levels of NRN1, ACTN4, EPHX4, RPH3A, SGTB, CPLX1, and SH3GL1 were associated with greater cognitive resilience, while higher levels of UBA1 were associated with less resilience. The study's findings suggest that these proteins may represent novel therapeutic targets for the treatment and prevention of Alzheimer disease and related dementias.

Key Takeaways

The study identified eight cortical proteins associated with cognitive resilience in older adults, providing potential therapeutic targets for Alzheimer disease and related dementias.
The proteins NRN1, ACTN4, EPHX4, RPH3A, SGTB, CPLX1, and SH3GL1 were associated with greater cognitive resilience, while UBA1 was associated with less resilience.
The study's findings support the idea that identifying protein targets that promote cognitive resilience can provide a complementary approach to protecting cognitive health in old age.

Corrections & amendments

This document is a correction notice for a previously published article in Nature, titled 'APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.' The original article investigated the role of APOE4 in impairing myelination through cholesterol dysregulation in oligodendrocytes, using single-nucleus RNA sequencing (snRNA-seq) on post-mortem brain tissue. The correction addresses the 'Isolation of nuclei from frozen post-mortem brain tissue' and 'Droplet-based snRNA-seq' sections of the Methods, clarifying that 8 of the 32 reported samples were taken from a previous study (Mathys et al., 2019) and reprocessed with newly generated data. The correction updates the Methods section in both HTML and PDF versions of the article to reflect this overlap.

Key Takeaways

The correction highlights the importance of transparency in sample usage and data processing in scientific research.
The original study's findings on APOE4's role in myelination impairment remain valid, but the correction provides a more accurate representation of the data's origin.
This correction notice demonstrates the ongoing efforts to refine and improve the accuracy of scientific literature, particularly in complex fields like Alzheimer's disease research.

Early Alzheimer's disease pathology in human cortex involves transient cell states

This study analyzed single-nucleus RNA sequencing data from cortical biopsies of living individuals with varying degrees of Alzheimer's disease (AD) pathology. The results identified cell states associated with early AD pathology, including a hyperactive state in upper-layer pyramidal neurons preceding degeneration, expanded microglial populations with AD-specific alterations, and a shared signature of differentially regulated genes associated with amyloid production in both oligodendrocytes and excitatory neurons. The study provides insights into the cellular perturbations underlying early AD pathology and highlights the importance of human biopsy tissue in understanding disease mechanisms.

Key Takeaways

The study identified a hyperactive state in upper-layer pyramidal neurons that precedes degeneration and is associated with the loss of a specific NDNF-expressing interneuron population early in disease progression.
Two activated microglial states were expanded in AD, one of which (GPNMB-EYA2) is shared between AD and Parkinson's disease, while the other (LPL-CD83) is AD-specific and shows high expression of TGFb signaling components.
Oligodendrocytes and excitatory neurons share a common signature of differentially regulated genes associated with amyloid production, which peaks in the earliest stages of amyloid deposition.
The study highlights the importance of human biopsy tissue in understanding disease mechanisms and identifies potential therapeutic targets for early intervention in AD.

Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles: Intracellular A 𝛃 and Synaptic Dysfunction

This study describes the development and characterization of a novel triple-transgenic mouse model (3 × Tg-AD) of Alzheimer's disease, which harbors PS1M146V, APPSwe, and tauP301L transgenes. The model progressively develops both amyloid-β plaques and neurofibrillary tangles in AD-relevant brain regions. The mice exhibit deficits in synaptic plasticity, including long-term potentiation (LTP), which occurs before extracellular amyloid-β deposition and tangles. The study suggests a novel pathogenic role for intraneuronal amyloid-β in synaptic dysfunction and provides a valuable model for evaluating potential AD therapeutics.

Key Takeaways

The 3 × Tg-AD mouse model recapitulates key features of Alzheimer's disease pathology, including amyloid-β plaques and neurofibrillary tangles, and exhibits synaptic dysfunction before overt pathology.
Intraneuronal amyloid-β accumulation is the earliest neuropathological manifestation and correlates with impairments in synaptic plasticity, including LTP deficits.
The study provides evidence that intraneuronal amyloid-β plays a pathogenic role in synaptic dysfunction, which is a proximal defect in the pathobiology of Alzheimer's disease.
The 3 × Tg-AD model is a valuable tool for studying the impact of amyloid-β and tau on synaptic plasticity and for evaluating the efficacy of anti-AD therapies.

High-Level Neuronal Expression of A b 1-42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation

This study investigates the relationship between amyloid beta (Aβ) levels, plaque formation, and synaptic deficits in transgenic mice expressing human amyloid protein precursor (hAPP). The results show that high levels of Aβ1-42 in mice expressing wild-type hAPP did not lead to plaque formation but were associated with decreased levels of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals. Across different transgenic lines, decreases in SYN-IR presynaptic terminals correlated with Aβ levels but not with hAPP levels or plaque load. The findings suggest that plaque-independent Aβ toxicity plays a key role in the pathogenesis of Alzheimer's disease-related neurodegeneration.

Key Takeaways

Aβ1-42 levels, not hAPP levels or plaque load, correlate with synaptic deficits.
High Aβ1-42 levels without plaque formation are synaptotoxic.
The Aβ1-42/Aβ1-40 ratio influences plaque formation, with Aβ1-40 potentially having an anti-amyloidogenic effect.

Environmental risk factors for dementia: a systematic review | BMC Geriatrics | Full Text

This systematic review examines the association between environmental risk factors and dementia. The review included 60 studies and found moderate evidence for air pollution, aluminium, silicon, selenium, pesticides, vitamin D, and electromagnetic fields as risk factors for dementia. The evidence for toxic heavy metals and occupational exposures was generally weak. The review highlights the need for further robust, longitudinal studies to confirm these associations and to explore the mechanisms underlying these relationships.

Key Takeaways

Air pollution, particularly nitrogen oxides, particulate matter, and ozone, is associated with an increased risk of dementia.
There is moderate evidence implicating aluminium, silicon, selenium, pesticides, vitamin D deficiency, and electric and magnetic fields as risk factors for dementia.
Further research is needed to confirm these associations and to explore the mechanisms underlying these relationships, considering the life course approach and critical periods of exposure.

The Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials - ScienceDirect

This document discusses the evolution of preclinical Alzheimer's disease (AD), focusing on the implications for prevention trials. It examines the amyloid debate, staging of preclinical AD, and the relationship between markers of amyloid and neurodegeneration (ND). The authors propose a hypothetical staging framework for preclinical AD based on biomarker status, including Aβ accumulation and ND markers. They discuss the promise of tau PET imaging as a valuable addition to preclinical AD trial designs. The document also explores the earliest cognitive changes associated with preclinical AD and the concept of resilience and reserve. The authors address issues around terminology, including the use of 'preclinical AD' and its implications. Finally, they discuss the implications for prevention trial design, highlighting the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the challenges of identifying individuals at risk for AD before significant Aβ accumulation occurs.

Key Takeaways

The convergence of Aβ and ND pathways accelerates further ND and is consequential to behavioral outcomes.
Tau PET imaging may prove to be a valuable addition to preclinical AD trial designs, potentially serving as a 'theragnostic' marker.
The A4 Study will acquire PET amyloid imaging, structural and fMRI, and CSF measures and Tau PET imaging in a subset, providing crucial information on individual risk of decline related to Aβ accumulation.
Identifying individuals with relatively low levels of Aβ accumulation who are in the rapid phase of accumulation may be a potential target for prevention trials.
The field needs to define the critical window for successful disease-modifying therapies, likely before the stage of clinical impairment when widespread, irreversible damage is already present.

Causes and Patterns of Dementia: An Update in the Era of Redefining Alzheimer's Disease | Annual Reviews

The document reviews the current understanding of dementia causes, risk factors, and changing patterns, shaped by the 2018 NIA-AA research framework for Alzheimer's disease (AD). It highlights the multifactorial etiology of dementia, the role of mixed pathologies, and neural reserve. The framework defines AD as a biological process measured by brain pathology or biomarkers. Many risk factors for Alzheimer's dementia are not related to AD pathology but to other pathologies or resilience. The prevalence of dementia is decreasing in Western countries, attributed to improved control of cardiovascular risk factors and increasing education levels. The document discusses the implications for drug development, public policy, and the need for a greater precision in terminology.

Key Takeaways

The 2018 NIA-AA research framework redefines Alzheimer's disease as a biological process, facilitating interventions in the asymptomatic space and accommodating multiple pathologies contributing to Alzheimer's dementia.
Most established risk factors for Alzheimer's dementia do not directly affect AD pathology; instead, they work through vascular or other pathologies, modify the relationship between pathology and dementia, or are independent of pathologies.
The decreasing age-specific risk of dementia in Western countries is attributed to changes in the prevalence of cerebrovascular pathologies or increased neural reserve, rather than changes in AD pathology.
The framework has implications for drug development, suggesting alternative avenues such as targeting neural reserve capacity, and for public policy, highlighting the importance of prevention through modifiable risk factors and neural reserve capacity.

Preparing to download ...

The document outlines the U.S. Department of Health and Human Services' (HHS) vulnerability disclosure policy, providing guidelines for securely reporting vulnerabilities in HHS systems. It details the process for identifying, reporting, and addressing potential security issues, emphasizing responsible disclosure practices. The policy aims to protect HHS systems and data by encouraging collaboration between the department and the cybersecurity community. It includes information on how to submit vulnerability reports, the expected response times, and the procedures for handling disclosed vulnerabilities. The document is intended for both internal HHS stakeholders and external parties, such as security researchers, who may identify vulnerabilities in HHS systems.

Key Takeaways

The HHS vulnerability disclosure policy promotes a collaborative approach to cybersecurity by encouraging responsible disclosure from both internal and external sources.
The policy outlines clear guidelines for reporting and handling vulnerabilities, ensuring timely and effective responses to potential security threats.
By establishing a formal process for vulnerability disclosure, HHS aims to enhance the security posture of its systems and protect sensitive data.

The Cellular Phase of Alzheimer's Disease

This document discusses the complex cellular phase of Alzheimer's disease (AD), challenging the traditional amyloid cascade hypothesis. The authors propose that AD is a multifaceted process involving feedback and feedforward mechanisms between various cell types, including neurons, astrocytes, microglia, and oligodendrocytes. The cellular phase is characterized by proteostatic stress, homeostatic cellular responses, and defective clearance mechanisms. The neurovascular unit, comprising endothelial cells, pericytes, and astrocytes, plays a crucial role in AD pathogenesis. Astrocytes are central players in the cellular phase, regulating synaptic plasticity, and modulating neuronal activity. Microglia and inflammation are also key components, with TREM2 and other genetic variants influencing disease risk. The authors emphasize the need for a holistic understanding of AD, incorporating advances in single-cell biology and cellular network analysis to develop effective therapeutic strategies.

Key Takeaways

The cellular phase of Alzheimer's disease involves complex interactions between multiple cell types, including neurons, astrocytes, microglia, and oligodendrocytes.
Defective clearance mechanisms, particularly in the neurovascular unit, contribute to disease progression.
Astrocytes play a crucial role in regulating synaptic plasticity and modulating neuronal activity, and their dysfunction is a key component of AD pathogenesis.
TREM2 and other genetic variants influence disease risk by modulating microglial function and inflammatory responses.

Frequently Asked Questions

How do copper deficiency patterns across different brain regions correlate with specific cognitive domains affected in early vs. late-stage AD, and could regional copper supplementation strategies be developed?
What is the relationship between ATP7B genetic variants, serum copper levels, and lithium treatment response in aMCI patients, and how could this inform personalized lithium dosing protocols?
How do GSK3β activity levels in different cell types (neurons, oligodendrocytes, microglia) change throughout AD progression, and which cellular targets would be most effective for therapeutic intervention?
What are the mechanistic connections between Wnt signaling dysregulation, metal homeostasis disruption, and microglial efferocytosis dysfunction in AD pathogenesis?
How do the proteomic signatures of cognitive resilience (NRN1, ACTN4, EPHX4, RPH3A, SGTB, CPLX1, SH3GL1, UBA1) relate to metal metabolism and GSK3β signaling pathways?
What is the temporal relationship between intracellular Aβ accumulation, synaptic dysfunction, and metal dysregulation in the 3xTg-AD model compared to human AD progression?
How do environmental metal exposures (lead, cadmium, manganese) interact with genetic risk factors (APOE4, TREM2 variants) to influence AD susceptibility and progression rates?
What are the cell-type-specific effects of lithium treatment on transcriptomic signatures in human iPSC-derived brain organoids compared to mouse models?
How do complexin-I and complexin-II protein levels correlate with metal homeostasis markers and GSK3β activity across different Braak stages?
What is the relationship between ACSL1+ microglial states, lipid droplet accumulation, and copper/zinc metabolism in APOE4/4 carriers versus other genotypes?