Tau mediates the reshaping of the transcriptional landscape toward intermediate Alzheimer’s disease stages DOI Creative Commons
Giacomo Siano, Martina Varisco, Marco Terrigno

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 3, 2025

Recent research revealed that Tau plays critical roles in various neuronal functions. We previously demonstrated destabilization and nuclear delocalization of alter the expression glutamatergic genes, mediating early damage. In this study, we discovered changes availability are linked to global alterations gene affect multiple pathways. Comparison with human temporal region showed Tau-dependent modulation closely resembles intermediate stages Alzheimer's disease (AD) precede definitive pathological condition. Furthermore, identified chromatin remodeling pathway as being significantly affected by both our cellular model AD brains, reductions heterochromatin markers. Our findings indicate is able globally transcriptome its subcellular unbalance development. addition, found architecture during progression AD. These results provide new insights into molecular mechanisms underlying development highlight central role contribution process.

Language: Английский

Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology DOI Creative Commons
Hansruedi Mathys, Zhuyu Peng, Carles A. Boix

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4365 - 4385.e27

Published: Sept. 1, 2023

Alzheimer's disease (AD) is the most common cause of dementia worldwide, but molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas aged human prefrontal cortex covering 2.3 million cells from postmortem brain samples 427 individuals with varying degrees AD pathology impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed coordinated increase cohesin complex DNA damage response factors in neurons oligodendrocytes, uncovered genes pathways associated high function, dementia, resilience to pathology. Furthermore, selectively vulnerable somatostatin inhibitory subtypes depleted AD, discovered two distinct groups that were more abundant preserved function late life, link

Language: Английский

Citations

243
Human microglial state dynamics in Alzheimer’s disease progression DOI Creative Commons
Na Sun, Matheus B. Victor, Yongjin Park

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4386 - 4403.e29

Published: Sept. 1, 2023

Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus transcriptomes epigenomes across 443 human subjects diverse Alzheimer's (AD) pathological phenotypes. We annotate 12 transcriptional states, including AD-dysregulated homeostatic, inflammatory, lipid-processing states. identify 1,542 AD-differentially-expressed genes, both microglia-state-specific disease-stage-specific alterations. By integrating epigenomic, transcriptomic, motif information, infer upstream regulators of cell gene-regulatory networks, enhancer-gene links, transcription-factor-driven state transitions. demonstrate that ectopic expression our predicted homeostatic-state activators induces homeostatic features in iPSC-derived microglia-like cells, while inhibiting inflammation can block inflammatory progression. Lastly, pinpoint the AD-risk genes differential their during AD Overall, provide insights underlying state-specific AD-stage-specific alterations at unprecedented resolution.

Language: Английский

Citations

174
Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration DOI Creative Commons
Vishnu Dileep, Carles A. Boix, Hansruedi Mathys

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4404 - 4421.e20

Published: Sept. 1, 2023

Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer's disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq human postmortem prefrontal cortex samples and found that excitatory AD were enriched for somatic mosaic gene fusions. Gene fusions particularly damage repair senescence signatures. In addition, structural variations burdened DSBs CK-p25 mouse model neurodegeneration. Neurons also had elevated levels cohesin along progressive multiscale disruption 3D organization aligned transcriptional changes synaptic, neuronal development, histone genes. Overall, this study demonstrates stability by as steps progression diseases.

Language: Английский

Citations

66
Integrated multimodal cell atlas of Alzheimer’s disease DOI Creative Commons
Mariano I. Gabitto, Kyle J. Travaglini, Victoria M. Rachleff

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 14, 2024

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression characterized by stereotyped accumulation proteinopathies, affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from BRAIN Initiative to study middle temporal gyrus cell types 84 donors with varying pathologies. This cohort includes 33 male 51 female donors, an average age at time death 88 years. We used quantitative neuropathology place along a pseudoprogression score. Pseudoprogression analysis revealed two phases: early phase slow increase pathology, presence inflammatory microglia, reactive astrocytes, loss somatostatin

Language: Английский

Citations

60
Cellular and pathological functions of tau DOI
C Bravo, Sarah Naguib, Li Gan

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 845 - 864

Published: July 16, 2024

Language: Английский

Citations

36
Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy DOI Creative Commons
Qiuyang Zheng, Xin Wang

Protein & Cell, Journal Year: 2024, Volume and Issue: unknown

Published: May 11, 2024

Abstract Alzheimer’s disease (AD), the leading cause of dementia, is characterized by accumulation amyloid plaques and neurofibrillary tangles in brain. This condition casts a significant shadow on global health due to its complex multifactorial nature. In addition genetic predispositions, development AD influenced myriad risk factors, including aging, systemic inflammation, chronic conditions, lifestyle, environmental exposures. Recent advancements understanding pathophysiology are paving way for enhanced diagnostic techniques, improved assessment, potentially effective prevention strategies. These discoveries crucial quest unravel complexities AD, offering beacon hope management treatment options millions affected this debilitating disease.

Language: Английский

Citations

24
Single-cell multiplex chromatin and RNA interactions in ageing human brain DOI Creative Commons
Xingzhao Wen, Zhifei Luo,

Wenxin Zhao

et al.

Nature, Journal Year: 2024, Volume and Issue: 628(8008), P. 648 - 656

Published: March 27, 2024

Abstract Dynamically organized chromatin complexes often involve multiplex interactions and sometimes chromatin-associated RNA 1–3 . Chromatin complex compositions change during cellular differentiation ageing, are expected to be highly heterogeneous among terminally differentiated single cells 4–7 Here we introduce the multinucleic acid interaction mapping in (MUSIC) technique for concurrent profiling of interactions, gene expression RNA–chromatin associations within individual nuclei. When applied 14 human frontal cortex samples from older donors, MUSIC delineated diverse cortical cell types states. We observed that nuclei exhibiting fewer short-range were correlated with both an ‘older’ transcriptomic signature Alzheimer’s disease pathology. Furthermore, type contacts between cis quantitative trait loci a promoter tends which these specifically affect their target gene. In addition, female exhibit XIST non-coding chromosome X, along spatial organizations X chromosomes. presents potent tool exploration architecture transcription at resolution tissues.

Language: Английский

Citations

23
Therapeutic targeting of senescent cells in the CNS DOI
Markus Rießland, Methodios Ximerakis, Andrew A. Jarjour

et al.

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 30, 2024

Language: Английский

Citations

12
Integrative proteomics identifies a conserved Aβ amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer’s disease DOI Creative Commons
Yona Levites, Eric B. Dammer,

Yong Ran

et al.

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(8), P. 101669 - 101669

Published: Aug. 1, 2024

Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare proteome network changes with the proteomes of amyloid β (Aβ)-depositing mice to identify conserved divergent networks identifying an Aβ responsome. Proteins most (M42) accumulate plaques, cerebrovascular (CAA), and/or dystrophic neuronal processes, overexpression two M42 proteins, midkine (Mdk) pleiotrophin (PTN), increases accumulation plaques CAA. proteins bind fibrils vitro, MDK PTN co-accumulate cardiac transthyretin amyloid. appear intimately linked deposition can regulate deposition, suggesting they are pathology modifiers thus putative therapeutic targets. We posit amyloid-scaffolded M42+ central mechanism mediating downstream pathophysiology AD.

Language: Английский

Citations

11
Gene networks and systems biology in Alzheimer's disease: Insights from multi‐omics approaches DOI Creative Commons
Negin Rahimzadeh, Shushrruth Sai Srinivasan, Jing Zhang

et al.

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

Citations

10