Disease-specific selective vulnerability and neuroimmune pathways in dementia revealed by single cell genomics

Jessica E. Rexach(University of California, Los Angeles), Yuyan Cheng(University of California, Los Angeles), Lawrence Chen(University of California, Los Angeles), Damon Polioudakis(University of California, Los Angeles), Li‐Chun Lin(University of California, San Francisco), Vivianne Mitri(University of California, Los Angeles), Andrew Elkins(University of California, Los Angeles), Anna Yin(University of California, Los Angeles), Daniela Calini(Roche (Switzerland)), Riki Kawaguchi(University of California, Los Angeles), Jing Ou(University of California, Los Angeles), Jerry I. Huang(University of California, Los Angeles), Christopher Kwesi O. Williams(University of California, Los Angeles), John Robinson(University of Pennsylvania), Stephanie E. Gaus(University of California, San Francisco), Salvatore Spina(University of California, San Francisco), Edward B. Lee(University of Pennsylvania), Lea T. Grinberg(University of California, San Francisco), Harry V. Vinters(University of California, Los Angeles), John Q. Trojanowski(University of Pennsylvania), William W. Seeley(University of California, San Francisco), Dheeraj Malhotra(Roche (Switzerland)), Daniel H. Geschwind(University of California, Los Angeles)
bioRxiv (Cold Spring Harbor Laboratory)
September 30, 2023
10.1101/2023.09.29.560245
Cited by 11Open Access
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Abstract

Summary/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 RNAseq and ATACseq in Alzheimer disease (AD), Frontotemporal degeneration (FTD), and Progressive Supranuclear Palsy (PSP), analyzing 40 participants, yielding over 1.4M cells from three brain regions ranging in vulnerability and pathological burden. We identify 35 shared disease-associated cell types and 14 that are disease-specific, replicating those previously identified in AD. Disease - specific cell states represent molecular features of disease-specific glial-immune mechanisms and neuronal vulnerability in each disorder, layer 4/5 intra-telencephalic neurons in AD, layer 2/3 intra-telencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We infer intrinsic disease-associated gene regulatory networks, which we empirically validate by chromatin footprinting. We find that causal genetic risk acts in specific neuronal and glial cells that differ across disorders, primarily non-neuronal cells in AD and specific neuronal subtypes in FTD and PSP. These data illustrate the heterogeneous spectrum of glial and neuronal composition and gene expression alterations in different dementias and identify new therapeutic targets by revealing shared and disease-specific cell states.

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