@article{bb7c453905214ee7b9105a65711d3158,
title = "Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology",
abstract = "Senescent cells contribute to pathology and dysfunction in animal models1. Their sparse distribution and heterogenous phenotype have presented challenges to their detection in human tissues. We developed a senescence eigengene approach to identify these rare cells within large, diverse populations of postmortem human brain cells. Eigengenes are useful when no single gene reliably captures a phenotype, like senescence. They also help to reduce noise, which is important in large transcriptomic datasets where subtle signals from low-expressing genes can be lost. Each of our eigengenes detected ∼2% senescent cells from a population of ∼140,000 single nuclei derived from 76 postmortem human brains with various levels of Alzheimer{\textquoteright}s disease (AD) pathology. More than 97% of the senescent cells were excitatory neurons and overlapped with neurons containing neurofibrillary tangle (NFT) tau pathology. Cyclin-dependent kinase inhibitor 2D (CDKN2D/p19) was predicted as the most significant contributor to the primary senescence eigengene. RNAscope and immunofluorescence confirmed its elevated expression in AD brain tissue. The p19-expressing neuron population had 1.8-fold larger nuclei and significantly more cells with lipofuscin than p19-negative neurons. These hallmark senescence phenotypes were further elevated in the presence of NFTs. Collectively, CDKN2D/p19-expressing neurons with NFTs represent a unique cellular population in human AD with a senescence-like phenotype. The eigengenes developed may be useful in future senescence profiling studies as they identified senescent cells accurately in snRNA-Seq datasets and predicted biomarkers for histological investigation.",
author = "Dehkordi, {Shiva Kazempour} and Jamie Walker and Eric Sah and Emma Bennett and Farzaneh Atrian and Bess Frost and Benjamin Woost and Bennett, {Rachel E.} and Orr, {Timothy C.} and Yingyue Zhou and Andhey, {Prabhakar S.} and Marco Colonna and Sudmant, {Peter H.} and Peng Xu and Minghui Wang and Bin Zhang and Habil Zare and Orr, {Miranda E.}",
note = "Funding Information: This work is supported by NIH/NIA (R01AG068293, R01AG057896, U01AG046170, RF1AG057440, R01AG057907, K99AG061259; P30AG062421; RF1AG051485, R21AG059176, and RF1AG059082 and T32AG021890), Cure Alzheimer{\textquoteright}s Fund, New Vision Research Charleston Conference for Alzheimer{\textquoteright}s Disease, and Veterans Affairs (IK2BX003804). We obtained ROSMAP data from the AD Knowledge Portal (https://adknowledgeportal.synapse.org). Study data were provided by the Rush Alzheimer{\textquoteright}s Disease Center, Rush University Medical Center, Chicago. Data generation was supported by National Institute on Aging (NIA) and grants RF1AG57473, P30AG10161, R01AG15819, R01AG17917, U01G46152, U01AG61356 and RF1AG059082. Additional phenotypic ROSMAP data can be requested at https://www.radc.rush.edu. We acknowledge the Texas Advanced Computing Center (TACC) at the University of Texas at Austin for providing high-performance computing resources: http://www.tacc.utexas.edu. We acknowledge the Biggs Institute Brain Bank and Massachusetts ADRC for providing postmortem human tissue for analyses. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: This work is supported by NIH/NIA (R01AG068293, R01AG057896, U01AG046170, RF1AG057440, R01AG057907, K99AG061259; P30AG062421; RF1AG051485, R21AG059176, and RF1AG059082 and T32AG021890), Cure Alzheimer{\textquoteright}s Fund, New Vision Research Charleston Conference for Alzheimer{\textquoteright}s Disease, and Veterans Affairs (IK2BX003804). We obtained ROSMAP data from the AD Knowledge Portal ( https://adknowledgeportal.synapse.org ). Study data were provided by the Rush Alzheimer{\textquoteright}s Disease Center, Rush University Medical Center, Chicago. Data generation was supported by National Institute on Aging (NIA) and grants RF1AG57473, P30AG10161, R01AG15819, R01AG17917, U01G46152, U01AG61356 and RF1AG059082. Additional phenotypic ROSMAP data can be requested at https://www.radc.rush.edu . We acknowledge the Texas Advanced Computing Center (TACC) at the University of Texas at Austin for providing high-performance computing resources: http://www.tacc.utexas.edu . We acknowledge the Biggs Institute Brain Bank and Massachusetts ADRC for providing postmortem human tissue for analyses. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
year = "2021",
month = dec,
doi = "10.1038/s43587-021-00142-3",
language = "English",
volume = "1",
pages = "1107--1116",
journal = "Nature Aging",
issn = "2662-8465",
number = "12",
}