Journal article
Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics
Cell, Vol.187(20), pp.5753-5774.e28
10/2024
DOI: 10.1016/j.cell.2024.08.019
PMCID: PMC12017262
PMID: 39265576
Abstract
The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer’s disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14 that are disease specific. Disease-specific cell states represent glial-immune mechanisms and selective neuronal vulnerability impacting layer 5 intratelencephalic neurons in AD, layer 2/3 intratelencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We identify disease-associated gene regulatory networks and cells impacted by causal genetic risk, which differ by disorder. These data illustrate the heterogeneous spectrum of glial and neuronal compositional and gene expression alterations in different dementias and identify therapeutic targets by revealing shared and disease-specific cell states.
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•Perform comparative genomic analysis of AD, bvFTD, and PSP at the single-cell level•Pinpoint markers and candidate drivers of selective neuronal vulnerability in dementia•Identify disorder-specific microglia, astrocyte, and oligodendrocyte glial-immune states•Causal genetic risk impacts disorder-specific gene regulatory networks and cells
Functional genomic analyses of multiple brain regions across three major neurodegenerative disorders involving tau pathology, AD, bvFTD, and PSP, at the single-cell level enables the identification of markers of neuronal vulnerability, glial states that vary across disease, and disorder-specific cellular differences in the expression and regulation of known-risk genes.
Details
- Title: Subtitle
- Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics
- Creators
- Jessica E. Rexach - University of California, Los AngelesYuyan Cheng - University of California, Los AngelesLawrence Chen - University of California, Los AngelesDamon Polioudakis - University of California, Los AngelesLi-Chun Lin - University of California, San FranciscoVivianne Mitri - University of California, Los AngelesAndrew Elkins - University of California, Los AngelesXia Han - University of California, Los AngelesMai Yamakawa - University of California, Los AngelesAnna Yin - University of California, Los AngelesDaniela Calini - Roche (Switzerland)Riki Kawaguchi - University of California, Los AngelesJing Ou - University of California, Los AngelesJerry Huang - University of California, Los AngelesChristopher Williams - University of California, Los AngelesJohn Robinson - University of PennsylvaniaStephanie E. Gaus - University of California, San FranciscoSalvatore Spina - University of California, San FranciscoEdward B. Lee - University of PennsylvaniaLea T. Grinberg - University of California, San FranciscoHarry Vinters - University of California, Los AngelesJohn Q. Trojanowski - University of PennsylvaniaWilliam W. Seeley - University of California, San FranciscoDheeraj Malhotra - Roche (United States)Daniel H. Geschwind - University of California, Los Angeles
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.187(20), pp.5753-5774.e28
- DOI
- 10.1016/j.cell.2024.08.019
- PMID
- 39265576
- PMCID
- PMC12017262
- NLM abbreviation
- Cell
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Publisher
- Elsevier Inc
- Grant note
- Roche PharmaceuticalsBrightFocusRainwater Charitable FoundationNIH: K08 NS105916, R01 AG075802, 5UG3NS104095, AG023501, AG019724, P01AG066597, P30AG072979, U19AG062418 John Douglas French Alzheimer's FoundationBluefield Project to Cure bvFTD
Funding for this work was provided by Roche Pharmaceuticals (D.H.G. and D.M.), BrightFocus (D.H.G. and J.E.R.), Rainwater Charitable Foundation (D.H.G. and W.W.S.), NIH grants (K08 NS105916 [J.E.R.], R01 AG075802 [J.E.R. and L.T.G.], and 5UG3NS104095 [D.H.G.] ), and John Douglas French Alzheimer's Foundation (J.E.R.). The UCSF Neurodegenerative Disease Brain Bank is supported by NIH grants AG023501 and AG019724, the Rainwater Charitable Foundation, and the Bluefield Project to Cure bvFTD. The University of Pennsylvania Center for Neurodegenerative Disease Research is supported by NIH grants P01AG066597, P30AG072979, and U19AG062418.
- Language
- English
- Electronic publication date
- 09/09/2024
- Date published
- 10/2024
- Academic Unit
- Neurology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984719237502771
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