Single-cell multiregion dissection of Alzheimer’s disease

Nature, Journal Year: 2024, Volume and Issue: 632(8026), P. 858 - 868

Published: July 24, 2024

Abstract Alzheimer’s disease is the leading cause of dementia worldwide, but cellular pathways that underlie its pathological progression across brain regions remain poorly understood 1–3 . Here we report a single-cell transcriptomic atlas six different in aged human brain, covering 1.3 million cells from 283 post-mortem samples 48 individuals with and without disease. We identify 76 cell types, including region-specific subtypes astrocytes excitatory neurons an inhibitory interneuron population unique to thalamus distinct canonical subclasses. vulnerable populations are depleted specific disease, provide evidence Reelin signalling pathway involved modulating vulnerability these neurons. develop scalable method for discovering gene modules, which use cell-type-specific modules altered annotate differences associated diverse variables. astrocyte program cognitive resilience pathology, tying choline metabolism polyamine biosynthesis preserved function late life. Together, our study develops regional ageing provides insights into vulnerability, response pathology.

Language: Английский

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Cell-type-specific effects of age and sex on human cortical neurons

Neuron, Journal Year: 2024, Volume and Issue: 112(15), P. 2524 - 2539.e5

Published: June 5, 2024

Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes with advanced age. Using single-nucleus multi-omic DNA methylation transcriptome sequencing (snmCT-seq) in frontal cortex from young adult aged donors, we found widespread age- sex-related variation specific neuron types. The proportion inhibitory SST- VIP-expressing neurons was reduced donors. Excitatory had more profound age-related their gene expression than cells. Hundreds genes involved synaptic activity, including EGR1, were less expressed adults. Genes located subtelomeric regions increased age correlated telomere length. We further mapped cell-type-specific sex differences X-inactivation escape genes. Multi-omic epigenomes transcriptomes provide new insight into the effects on human neurons.

Language: Английский

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Reactive astrocytes secrete the chaperone HSPB1 to mediate neuroprotection

Science Advances, Journal Year: 2024, Volume and Issue: 10(12)

Published: March 20, 2024

Molecular chaperones are protective in neurodegenerative diseases by preventing protein misfolding and aggregation, such as extracellular amyloid plaques intracellular tau neurofibrillary tangles Alzheimer's disease (AD). In addition, AD is characterized an increase astrocyte reactivity. The chaperone HSPB1 has been proposed a marker for reactive astrocytes; however, its astrocytic functions neurodegeneration remain to be elucidated. Here, we identify that secreted from astrocytes exert non-cell-autonomous functions. We show human brain, levels cluster around plaques, well the adjacent space. Moreover, conditions mimic inflammatory response, secretion. Concomitantly, neurons can uptake astrocyte-secreted HSPB1, which accompanied attenuation of response reduced pathological inclusions. Our findings highlight mechanism encompasses secretion typically regarded intracellular.

Language: Английский

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Gene networks and systems biology in Alzheimer's disease: Insights from multi‐omics approaches

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(5), P. 3587 - 3605

Published: March 27, 2024

Despite numerous studies in the field of dementia and Alzheimer's disease (AD), a comprehensive understanding this devastating remains elusive. Bulk transcriptomics have provided insights into underlying genetic factors at high level. Subsequent technological advancements focused on single-cell omics, encompassing techniques such as RNA sequencing epigenomics, enabling capture transcripts chromatin states single cell or nucleus resolution. Furthermore, emergence spatial omics has allowed study gene responses vicinity amyloid beta plaques across various brain regions. With vast amount data generated, utilizing regulatory networks to comprehensively become essential. This review delves some employed AD, explores discoveries made using these techniques, provides future field.

Language: Английский

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Functional insight into East Asian–specific genetic risk loci for Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(2)

Published: Feb. 1, 2025

Abstract INTRODUCTION The functional study of genetic risk factors for Alzheimer's disease (AD) provides insights into the underlying mechanisms and identification potential therapeutic targets. Investigating AD‐associated loci identified in East Asian populations using single‐nucleus RNA‐sequencing data may identify novel contributors. METHODS Cell type–specific expression quantitative trait (eQTL) peak‐to‐gene links were used to genes associated with 26 from seven genome‐wide association studies (GWAS) AD Asians. RESULTS KCNJ6 MAPK1IP1L as significant eQTLs loci. peaks related four genes, CLIC4 being connected across different cell types. Genes European GWAS interacted within networks enriched pathology pathways astrocytes. DISCUSSION Our findings suggest providing insight architecture Highlights Integrated analysis was performed. (eQTLs) assay transposase‐accessible chromatin genes. An variant linked through an oligodendrocyte progenitor cell–specific eQTL. maps open chromatin, six Astrocyte differentially expressed by are

Language: Английский

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Protracted neuronal recruitment in the temporal lobes of young children

Nature, Journal Year: 2023, Volume and Issue: 626(8001), P. 1056 - 1065

Published: Dec. 20, 2023

Abstract The temporal lobe of the human brain contains entorhinal cortex (EC). This region is a highly interconnected integrative hub for sensory and spatial information; it also has key role in episodic memory formation main source cortical hippocampal inputs 1–4 . EC continues to develop during childhood 5 , but neurogenesis neuronal migration are widely considered be complete by birth. Here we show that many young neurons migrating into postnatal adjacent regions, with large tangential stream persisting until age around one year radial dispersal continuing two three years age. By contrast, found no equivalent rhesus macaques ( Macaca mulatta ). Immunostaining single-nucleus RNA sequencing ganglionic eminence germinal zones, revealed most cells derived from caudal become LAMP5 + RELN inhibitory interneurons. These late-arriving interneurons could continue shape processing information well life, when children actively interacting their environment. first regions affected Alzheimer’s disease, previous work linked cognitive decline loss 6,7 Our investigation reveals these arrive through major migratory early childhood.

Language: Английский

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Molecular hallmarks of excitatory and inhibitory neuronal resilience and resistance to Alzheimer's disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer's disease (AD) pathology, known as resilience. Understanding the molecular mechanisms that protect these can identify therapeutic targets for AD dementia. This study aims to define and cellular signatures resilience, protection resistance, by integrating genetics, bulk RNA, single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, control individuals. We analyzed Religious Order Study Rush Memory Aging Project (ROSMAP), including (n=631) multi-regional single nucleus (n=48) sequencing. Subjects were categorized into based on β-amyloid tau status. identified prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, composition distribution. Transcriptomic results, supported GWAS-derived polygenic risk scores, place resilience an intermediate state in continuum. Tissue-level analysis revealed 43 genes enriched nucleic acid metabolism signaling differentially expressed between Only GFAP (upregulated) KLF4 (downregulated) showed differential expression compared controls. Cellular involved reorganization protein folding degradation pathways, with downregulation Hsp90 selective upregulation Hsp40, Hsp70, Hsp110 families excitatory neurons. Excitatory neuronal subpopulations entorhinal cortex (ATP8B1+ MEF2C high ) exhibited unique through neurotrophin (modulated LINGO1) angiopoietin (ANGPT2/TEK) pathways. MEF2C, ATP8B1, RELN key markers resilient populations, characterized vulnerability AD. Protective rare variant enrichment highlighted vulnerable somatostatin (SST) inhibitory interneurons, validated immunofluorescence showing co-expression associated RBFOX1 KIF26B SST+ neurons dorsolateral prefrontal cortex. The maintenance excitatory-inhibitory balance emerges a characteristic hallmarks Resilience include preservation function, excitatory/inhibitory balance, activation protective Specific appear play central role mediating while subset SST interneurons likely provide compensation against AD-associated dysregulation. offers framework leverage natural mitigate neurodegeneration preserve cognition

Language: Английский

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Fast evolutionary turnover and overlapping variances of sex-biased gene expression patterns defy a simple binary classification of sexes

Published: March 28, 2025

The phenotypic differences between the sexes are generated by genes with sex-biased expression. These range from a few major regulators to large numbers of organ-specific effector in sexually mature individuals. We explore variation and evolutionary patterns these dataset natural populations sub-species species mice across an distance two million years. Within short phylogenetic distances, we find faster turnover gene expression compared non-sex-biased adaptive protein evolution for that given taxon. show occur only subset co-expression modules each organ taxa occurs often within main modules. Given our is first animals was combined population genetic context, were interested study within-group variances somatic gonadal tissues their turnover. To visualize individual variances, have developed index (SBI) represents cumulative all organ. SBI distributions can close binary overlapping sexes. They do not correlate organs same individuals, thus supporting mosaic model sex-determination Comparison data humans shows fewer strongly conclude subject fast evolution, no long-term stability male or female characteristics.

Language: Английский

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Transcriptomic analyses of human brains with Alzheimer’s disease identified dysregulated epilepsy-causing genes

Epilepsy & Behavior, Journal Year: 2025, Volume and Issue: 168, P. 110421 - 110421

Published: April 17, 2025

Language: Английский

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Cerebellar Pathology in Forensic and Clinical Neuroscience

Ageing Research Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102697 - 102697

Published: Feb. 1, 2025

Language: Английский

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