Biology subjects

Klein, H.-U.

Publications and source records attributed to Klein, H.-U..

At least 19 recordsLinked to original sources

bioRxiv2026

High-Dimensional Multi-omic Mapping of Post-Mortem Human Brain Using Iterative Indirect Immunofluorescence Imaging on Xenium-Processed Tissues

Spatial transcriptomics approaches provide crucial insights into gene expression distribution within intact tissue architecture, but they encounter limitations in detecting morphologically complex cell types, assessing their spatial associations with pathology, and accurately annotating cell types using RNA data alone. Therefore, we developed a robust post-processing workflow integrating Xenium spatial technology with iterative indirect immunofluorescence imaging (4i) on formalin-fixed paraffin-embedded (FFPE) human brain tissue. The post-Xenium 4i protocol presented here allows multi-omic tissue mapping, enabling deeper investigation of pathological microenvironments defined by the spatial distribution of neuropathological hallmarks and enrichment of specific cell populations. We applied this workflow on calcarine cortex tissue sections where cerebral amyloid angiopathy (CAA) burden is present, in addition to amyloid plaques and tau pathology, generating a 15-plex image that captures the complexity of the pathological microenvironment.

neuroscience↗

bioRxiv2025

A factor-based analysis of individual human microglia uncovers regulators of an Alzheimer-related transcriptional signature

Human microglial heterogeneity is only beginning to be appreciated at the molecular level. Here, we present a large, single-cell atlas of expression signatures from 441,088 live microglia broadly sampled across a diverse set of brain regions and neurodegenerative and neuroinflammatory diseases obtained from 161 donors sampled at autopsy or during a neurosurgical procedure. Using single-cell hierarchical Poisson factorization (scHPF), we derived a 23-factor model for continuous gene expression signatures across microglia which capture specific biological processes (e.g., metabolism, phagocytosis, antigen presentation, inflammatory signaling, disease-associated states). Using external datasets, we evaluated the aspects of microglial phenotypes that are encapsulated in various in vitro and in vivo microglia models and identified and replicated the role of two factors in human postmortem tissue of Alzheimers disease (AD). Further, we derived a complex network of transcriptional regulators for all factors, including regulators of an AD-related factor enriched for the mouse disease-associated microglia 2 (DAM2) signature: ARID5B, CEBPA, MITF, and PPARG. We replicated the role of these four regulators in the AD-related factor and then designed a multiplexed MERFISH panel to assess our microglial factors using spatial transcriptomics. We find that, unlike cells with high expression of the interferon-response factor, cells with high expression of the AD DAM2-like factor are widely distributed in neocortical tissue. We thus propose a novel analytic framework that provides a taxonomic approach for microglia that is more biologically interpretable and use it to uncover new therapeutic targets for AD.

neuroscience↗

bioRxiv2025

PLXNB1 and other signaling drives a pathologic astrocyte state contributing to cognitive decline in Alzheimer's Disease

Alzheimers disease (AD) is marked by the coordinated emergence of disease-associated cell states across multiple cell types. Here, we first performed a meta-analysis of single-nucleus transcriptomic (snRNAseq) data from 869 brains of diverse decedents, confirming the critical role of an SLC38A2highSMTNhighCACNA1Dhighastrocyte subset, Astrocyte 10 (Ast10), in AD and aging-related cognitive decline. We then investigated the signaling drivers of Ast10s emergence in the aging brain, focusing on interactions among microglial and astrocytic subsets. Analysis of the snRNAseq data prioritized a set of ligands and receptors that are robustly predictive of Ast10 proportions across participants, and we confirm our predictions in multiple studies. Independent validation with spatial transcriptomics reveals striking colocalization of these prioritized ligands with the Ast10 signature in AD brain tissue, but not with other astrocytic states. Genetic ablation of a top receptor PLXNB1 in murine and human iPSC-derived astrocytes decreased the Ast10 signature, confirming its regulatory role. Finally, we find that Ast10 may contribute to cognitive decline through synaptic loss and is associated with cognitive decline independent of AD. Thus, Ast10 and its regulators are potential points of convergence for multiple neurodegenerative mechanisms and may be promising targets for therapeutic development to preserve cognitive function.

neuroscience↗

bioRxiv2024

Spatial Transcriptomic Analysis Identifies a SERPINA3-Expressing Astrocytic State Associated with the Human Neuritic Plaque Microenvironment

Single-nucleus transcriptomic studies have revealed glial cell states associated with Alzheimers disease; however, these nuclei are dissociated from the complex architecture of the human neocortex. Here, we successfully performed an unbiased distance-based analytic strategy on spatially-registered transcriptomic data. Leveraging immunohistochemistry in the same tissue section, our analyses prioritized SERPINA3 and other genes, such as metallothioneins, as altered in the vicinity of neuritic amyloid plaques. Results were validated at the protein level by immunofluorescence, highlighting that a reactive SERPINA3+ astrocyte subtype, Ast.5, plays a role in the plaque microenvironment.

neuroscience↗

bioRxiv2023

Psychosocial experiences are associated with human brain mitochondrial biology

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies heavily on energy transformation by mitochondria oxidative phosphorylation (OxPhos), and two main lines of evidence bi-directionally link mitochondria as both targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and possibly mood states alter multiple aspects of mitochondrial biology; and on the other hand, functional variations in mitochondrial OxPhos capacity alter social behavior, stress reactivity, and mood. However, knowledge on whether positive or negative psychosocial exposures and experiences are linked to mitochondrial biology in the human brain is currently unknown. By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we found that positive experiences (e.g. higher well-being) are linked to greater abundance of the mitochondrial OxPhos machinery, whereas negative experiences (e.g. higher negative mood) are linked to lower OxPhos protein content. Combined, psychosocial factors explained 18% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. To increase the sensitivity of our approach, we next interrogated mitochondrial psychobiological associations in specific neuronal and non-neuronal brain cells with single-nucleus RNA sequencing. These results revealed strong cell type specific associations, particularly between positive psychosocial experiences and molecular mitochondrial phenotypes in glial cells, whereas neurons tended to show opposite associations. Accordingly, in bulk transcriptomic analyses where all cells are pooled, these RNA-based associations were masked. Thus, our results highlight the likely underestimation of effect sizes in bulk brain tissues, and document novel cell type specific mitochondrial psychobiological associations in the human brain. Cell type specific mitochondrial recalibrations represent a potential psychobiological pathway linking positive and negative psychosocial experiences to human brain biology. Significance statementPsychosocial experiences predict health trajectories, but the underlying mechanism remains unclear. We found that positive psychosocial experiences are linked to greater abundance of the mitochondrial energy transformation machinery, whereas negative experiences are linked to lower abundance. Overall, we found that psychosocial experiences explain 18% of the variance in abundance of complex I proteins, the main entry point of the mitochondrial oxidative phosphorylation (OxPhos) system. At single-cell resolution using single nucleus transcriptomics, positive psychosocial experiences were particularly related to glial cell mitochondrial phenotypes. Opposite associations between glial cells and neurons were naturally masked in bulk transcriptomic analyses. Our results suggest that mitochondrial recalibrations in specific brain cell types may represent a potential psychobiological pathway linking psychosocial experiences to human brain health.

cell biology↗

bioRxiv2023

ZCCHC17 modulates neuronal RNA splicing and supports cognitive resilience in Alzheimer's disease

ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimers Disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis. Co-immunoprecipitation of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17s binding partners are enriched for RNA splicing proteins. ZCCHC17 knockdown results in widespread RNA splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression correlates with cognitive resilience in AD patients, and we uncover an APOE4 dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, a majority of ZCCHC17 interactors also co-IP with known tau interactors, and we find significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17s role in neuronal RNA processing and its interaction with pathology and cognitive resilience in AD, and suggest that maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology. SignificanceAbnormal RNA processing is an important component of AD pathophysiology. We show here that ZCCHC17, a previously identified putative master regulator of synaptic dysfunction in AD, plays a role in neuronal RNA processing, and illustrate that ZCCHC17 dysfunction is sufficient to explain some of the splicing abnormalities seen in AD brain tissue, including synaptic gene splicing abnormalities. Using data from human patients, we demonstrate that ZCCHC17 mRNA levels correlate with cognitive resilience in the setting of AD pathology. These results suggest that maintenance of ZCCHC17 function may be a therapeutic strategy for supporting cognitive function in AD patients, and motivate future work examining a possible role of abnormal RNA processing in AD-related cognitive decline.

neuroscience↗

bioRxiv2023

Cell-type-specific regulation of APOE levels in human neurons by the Alzheimer's disease risk gene SORL1

SORL1 is strongly implicated in the pathogenesis of Alzheimers disease (AD) through human genetic studies that point to an association of reduced SORL1 levels with higher risk for AD. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null iPSCs were generated, followed by differentiation to neuron, astrocyte, microglia, and endothelial cell fates. Loss of SORL1 led to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. Intriguingly, SORL1 loss led to a dramatic neuron-specific reduction in APOE levels. Further, analyses of iPSCs derived from a human aging cohort revealed a neuron-specific linear correlation between SORL1 and APOE RNA and protein levels, a finding validated in human post-mortem brain. Pathway analysis implicated intracellular transport pathways and TGF- {beta}/SMAD signaling in the function of SORL1 in neurons. In accord, enhancement of retromer-mediated trafficking and autophagy rescued elevated phospho-tau observed in SORL1 null neurons but did not rescue APOE levels, suggesting that these phenotypes are separable. Stimulation and inhibition of SMAD signaling modulated APOE RNA levels in a SORL1-dependent manner. These studies provide a mechanistic link between two of the strongest genetic risk factors for AD.

neuroscience↗

bioRxiv2023

Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate in aging fibroblasts

The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in non-human species 1-3 and recently demonstrated to occur in rare instances from one human generation to the next 4. Here we investigated numtogenesis dynamics in humans in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples from different individuals. Compared to circulating immune cells (n=389), post-mitotic brain tissue (n=798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, more brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts using a repeated-measures WGS design in a human fibroblast model that recapitulates several molecular hallmarks of aging 5. These longitudinal experiments revealed a gradual accumulation of one Numt every [~]13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7- fold faster than healthy donors. Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human post-mitotic tissues produce functionally-relevant human Numts over timescales shorter than previously assumed.

genomics↗

bioRxiv2023

demuxmix: Demultiplexing oligonucleotide-barcoded single-cell RNA sequencing data with regression mixture models

MotivationDroplet-based single-cell RNA sequencing (scRNA-seq) is widely used in biomedical research to interrogate the transcriptomes of single cells on a large scale. Pooling and processing cells from different samples together can reduce costs and batch effects. In order to pool cells, cells are often first labeled with hashtag oligonucleotides (HTOs). These HTOs are sequenced along with the cells RNA in the droplets and are subsequently used to computationally assign each droplet to its sample of origin, which is referred to as demultiplexing. Accurate demultiplexing is crucial and can be challenging due to background HTOs, low-quality cells/cell debris, and multiplets. ResultsA new demultiplexing method, demuxmix, based on negative binomial regression mixture models is introduced. The method implements two significant improvements. First, demuxmixs probabilistic classification framework provides error probabilities for droplet assignments that can be used to discard uncertain droplets and inform about the quality of the HTO data and the demultiplexing success. Second, demuxmix utilizes the positive association between detected genes in the RNA library and HTO counts to explain parts of the variance in the HTO data resulting in improved droplet assignments. The improved performance of demuxmix compared to existing demultiplexing methods is assessed on real and simulated data. Finally, the feasibility of accurately demultiplexing experimental designs where non-labeled cells are pooled with labeled cells is demonstrated. AvailabilityR/Bioconductor package demuxmix (https://doi.org/doi:10.18129/B9.bioc.demuxmix)

bioinformatics↗

bioRxiv2023

Multi-region brain transcriptomes uncover two subtypes of aging individuals with differences in Alzheimer risk and the impact of APOEe4

The heterogeneity of the older population suggests the existence of subsets of individuals which share certain brain molecular features and respond differently to risk factors for Alzheimers disease, but this population structure remains poorly defined. Here, we performed an unsupervised clustering of individuals with multi-region brain transcriptomes to assess whether a broader approach, simultaneously considering data from multiple regions involved in cognition would uncover such subsets. We implemented a canonical correlation-based analysis in a Discovery cohort of 459 participants from two longitudinal studies of cognitive aging that have RNA sequence profiles in three brain regions. 690 additional participants that have data in only one or two of these regions were used in the Replication effort. These clustering analyses identified two meta-clusters, MC-1 and MC-2. The two sets of participants differ primarily in their trajectories of cognitive decline, with MC-2 having a delay of 3 years to the median age of incident dementia. This is due, in part, to a greater impact of tau pathology on neuronal chromatin architecture and to broader brain changes including greater loss of white matter integrity in MC-1. Further evidence of biological differences includes a significantly larger impact of APOE{varepsilon}4 risk on cognitive decline in MC-1. These findings suggest that our proposed population structure captures an aspect of the more distributed molecular state of the aging brain that either enhances the effect of risk factors in MC-1 or of protective effects in MC-2. These observations may inform the design of therapeutic development efforts and of trials as both become increasingly more targeted molecularly. One Sentence Summary: There are two types of aging brains, with one being more vulnerable to APOE{varepsilon}4 and subsequent neuronal dysfunction and cognitive loss.

neuroscience↗

bioRxiv2022

Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex

The relationship between genetic variation and gene expression in individual brain cell types and subtypes has remained elusive. Here, we generated single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of 424 individuals of advanced age; analyzing 1.5 million nuclear transcriptomes, we assessed the effect of genetic variants on RNA expression in cis (cis-eQTL) for 7 cell types and 81 cell subtypes. This effort identified 10,004 eGenes at the cell type level and 8,138 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer pathology, accounting for the effect of APOE{varepsilon}4, providing mechanistic insights into both pathologies. While eQTLs are readily detected, only a TMEM106B variant robustly affects the proportion of cell subtypes. Integration of these results with GWAS highlighted the targeted cell type and likely causal gene within susceptibility loci for Alzheimers, Parkinsons, schizophrenia, and educational attainment.

genomics↗

bioRxiv2022

Cell type- and state- resolved immune transcriptomic profiling identifies glucocorticoid-responsive molecular defects in multiple sclerosis T cells

The polygenic and multi-cellular nature of multiple sclerosis (MS) immunopathology necessitates cell-type-specific molecular studies in order to improve our understanding of the diverse mechanisms underlying immune cell dysfunction in MS. Here, by generating a dataset of 1,075 transcriptomes from 209 participants (167 MS and 42 healthy), we assessed MS-associated transcriptional changes in six implicated cell-type-states: naive and memory helper T cells and classical monocytes purified from peripheral blood, each in their primary (ex vivo, unstimulated) and in vitro stimulated states. Our data suggest that primary profiles show larger MS-associated differences than the post-stimulation contexts. We further identified shared and distinct changes in individual genes, biological pathways, and co-expressed gene modules in MS T cells and monocytes, and prioritized genes such as ZBTB16 as MS-associated regulators in both cell types. Of six identified MS-associated co-expressed gene modules, three (two lymphoid and one myeloid) were replicated in independent data from peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages. A subsequent in silico drug screen prioritized small-molecule compounds for reversing the perturbation of the MS-associated modules. The effects of glucocorticoid receptor agonists as the top-identified therapeutic class for the replicated T cell modules were validated using targeted in silico analyses and in vitro experiments, suggesting the coordinated dysregulation of glucocorticoid-responsive genes in MS T cells. In summary, our study identifies and validates individual genes and co-expressed gene modules from T and myeloid cells that are perturbed in MS, offering new targets for therapeutic discovery and biomarker development to guide the management of MS.

genomics↗

bioRxiv2022

A cross-disease human microglial framework identifies disease-enriched subsets and tool compounds for microglial polarization.

Human microglia play a pivotal role in neurological diseases, but few targeted therapies that directly modulate microglial state or function exist due to an incomplete understanding of microglial heterogeneity. We use single-cell RNA sequencing to profile live human microglia from autopsies or surgical resections across diverse neurological diseases and central nervous system regions. We observe a central divide between oxidative and heterocyclic metabolism and identify subsets associated with antigen presentation, motility, and proliferation. Specific subsets are enriched in susceptibility genes for neurodegenerative diseases or the disease-associated microglial signature. We validate subtypes in situ with an RNAscope-immunofluorescence pipeline and leverage our dataset as a classification resource, finding that iPSC model systems recapitulate substantial in vivo heterogeneity. Finally, we identify and validate candidates for chemically inducing subtype-specific states in vitro, showing that Camptothecin downregulates the transcriptional signature of disease-enriched subsets and upregulates a signature previously shown to be depleted in Alzheimers.

neuroscience↗

bioRxiv2021

Mitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain

Mitochondrial respiratory chain (RC) function requires the stoichiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimers disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2-4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.

cell biology↗

bioRxiv2020

Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer's disease risk in humans

INTRODUCTIONNot all APOE {varepsilon}4 carriers who survive to advanced age develop Alzheimers disease (AD); factors attenuating the risk of {varepsilon}4 on AD may exist. METHODSGuided by the top {varepsilon}4-attenuating signals from methylome-wide association analyses (N=572, {varepsilon}4+ and {varepsilon}4-) of neurofibrillary tangles and neuritic plaques, we conducted a meta-analysis for pathological AD within the {varepsilon}4+ subgroups (N=235) across four independent collections of brains. Cortical RNA-seq and microglial morphology measurements were used in functional analyses. RESULTSThree out of the four significant CpG dinucleotides were captured by one principle component (PC1), which interacts with {varepsilon}4 on AD, and is associated with expression of innate immune genes and activated microglia. In {varepsilon}4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 58% (OR=2.39, 95%CI=[1.64,3.46], P=7.08x10-6). DISCUSSIONAn epigenomic factor associated with a reduced proportion of activated microglia appears to attenuate the risk of {varepsilon}4 on AD.

neuroscience↗

bioRxiv2019

BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 implicated in Tau pathology

Identified as an Alzheimers disease (AD) susceptibility gene by genome wide-association studies, BIN1 has 10 isoforms that are expressed in the Central Nervous System (CNS). The distribution of these isoforms in different cell types, as well as their role in AD pathology still remains unclear. Utilizing antibodies targeting specific BIN1 epitopes in human postmortem tissue and analyzing RNA expression data from purified microglia, we identified three isoforms expressed specifically in neurons (isoforms 1, 2 and 3) and four isoforms expressed in microglia (isoforms 6, 9, 10 and 12). The abundance of selected peptides, which correspond to groups of BIN1 protein isoforms, was measured in dorsolateral prefrontal cortex, and their relation to neuropathological features of AD was assessed. Peptides contained in exon 7 of BIN1s N-BAR domain were found to be significantly associated with AD-related traits and, particularly, tau pathology. Since only isoforms 1, 2 and 3 contain exon 7, it appears that decreased protein expression of the N-BAR domain of BIN1 is associated with greater accumulation of tau pathology and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit. These effects are independent of the BIN1 AD risk variant, suggesting that targeting specific BIN1 isoforms might be a novel therapeutic approach to prevent the accumulation of tau pathology.

cell biology↗

bioRxiv2019

Meta-analysis of the human brain transcriptome identifies heterogeneity across human AD coexpression modules robust to sample collection and methodological approach

Alzheimers disease (AD) is a complex and heterogenous brain disease that affects multiple inter-related biological processes. This complexity contributes, in part, to existing difficulties in the identification of successful disease-modifying therapeutic strategies. To address this, systems approaches are being used to characterize AD-related disruption in molecular state. To evaluate the consistency across these molecular models, a consensus atlas of the human brain transcriptome was developed through coexpression meta-analysis across the AMP-AD consortium. Consensus analysis was performed across five coexpression methods used to analyze RNA-seq data collected from 2114 samples across 7 brain regions and 3 research studies. From this analysis, five consensus clusters were identified that described the major sources of AD-related alterations in transcriptional state that were consistent across studies, methods, and samples. AD genetic associations, previously studied AD-related biological processes, and AD targets under active investigation were enriched in only three of these five clusters. The remaining two clusters demonstrated strong heterogeneity between males and females in AD-related expression that was consistently observed across studies. AD transcriptional modules identified by systems analysis of individual AMP-AD teams were all represented in one of these five consensus clusters except ROS/MAP-identified Module 109, which was specific for genes that showed the strongest association with changes in AD-related gene expression across consensus clusters. The other two AMP-AD transcriptional analyses reported modules that were enriched in one of the two sex-specific Consensus Clusters. The fifth cluster has not been previously identified and was enriched for genes related to proteostasis. This study provides an atlas to map across biological inquiries of AD with the goal of supporting an expansion in AD target discovery efforts.

systems biology↗

bioRxiv2018

Epigenome-wide study uncovers tau pathology-driven changes of chromatin organization in the aging human brain

Accumulation of tau and amyloid-{beta} are two pathologic hallmarks of Alzheimers disease (AD). Here, we conducted an epigenome-wide association study using the H3K9 acetylation (H3K9Ac) mark in 669 aged human prefrontal cortices: in contrast to amyloid-{beta}, tau protein burden had a broad effect on the epigenome, affecting 5,590 out of 26,384 H3K9Ac domains. Tau-related alterations aggregated in large genomic segments reflecting spatial chromatin organization, and the magnitude of these effects correlated with the segments nuclear lamina association. We confirmed the functional relevance of these chromatin changes by demonstrating (1) consistent transcriptional changes in three independent datasets and (2) similar findings in two AD mouse models. Finally, we found that tau overexpression in iPSC-derived neurons disrupted chromatin organization and that these effects could be blocked by a small molecule predicted to reverse the tau effect. Thus, we report large-scale tau-driven chromatin rearrangements in the aging human brain that may be reversible with HSP90 inhibitors.

neuroscience↗