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Fröhlich, A.S.* ; Gerstner, N. ; Gagliardi, M.* ; Ködel, M.* ; Yusupov, N.* ; Matosin, N.* ; Czamara, D.* ; Sauer, S.* ; Roeh, S.* ; Murek, V.* ; Chatzinakos, C.* ; Daskalakis, N.P.* ; Knauer-Arloth, J. ; Ziller, M.J.* ; Binder, E.B.*

Single-nucleus transcriptomic profiling of human orbitofrontal cortex reveals convergent effects of aging and psychiatric disease.

Nat. Neurosci. 27, 2021-2032 (2024)

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Aging is a complex biological process and represents the largest risk factor for neurodegenerative disorders. The risk for neurodegenerative disorders is also increased in individuals with psychiatric disorders. Here, we characterized age-related transcriptomic changes in the brain by profiling ~800,000 nuclei from the orbitofrontal cortex from 87 individuals with and without psychiatric diagnoses and replicated findings in an independent cohort with 32 individuals. Aging affects all cell types, with LAMP5⁺LHX6⁺ interneurons, a cell-type abundant in primates, by far the most affected. Disrupted synaptic transmission emerged as a convergently affected pathway in aged tissue. Age-related transcriptomic changes overlapped with changes observed in Alzheimer's disease across multiple cell types. We find evidence for accelerated transcriptomic aging in individuals with psychiatric disorders and demonstrate a converging signature of aging and psychopathology across multiple cell types. Our findings shed light on cell-type-specific effects and biological pathways underlying age-related changes and their convergence with effects driven by psychiatric diagnosis.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Gene-expression; Quantile Normalization; Bioconductor Package; Alzheimers-disease; Brain; Age; Neurodegeneration; Association; Microglia; Lingo-1

ISSN (print) / ISBN 1097-6256

e-ISSN 1546-1726

Journal Nature Neuroscience

Quellenangaben Volume: 27, Issue: 10, Pages: 2021-2032

Publisher Nature Publishing Group

Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)

Grants National Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health
Hope for Depression Research Foundation
BMBF eMED program grant DINGS
Alexander von Humboldt Foundation
Joachim Herz Foundation - Else-Kroener-Fresenius Foundation
Brain & Behavior Research Foundation
National Institute of Mental Health
New South Wales Brain Tissue Resource Centre at the University of Sydney
University of Sydney
Nathalie Gerstner is supported by the Joachim Herz Foundation.