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Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology
Shiva Kazempour Dehkordi 1 2, Jamie Walker 1, Eric Sah 3, Emma Bennett 3, Farzaneh Atrian 2 4, Bess Frost 1 2 4, Benjamin Woost 5, Rachel E Bennett 5, Timothy C Orr 6, Yingyue Zhou 7, Prabhakar S Andhey 7, Marco Colonna 7, Peter H Sudmant 8, Peng Xu 9 10 11, Minghui Wang 9 10 11, Bin Zhang 9 10 11 12, Habil Zare 1 2, Miranda E Orr 3 13
...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's disease (AD) pathology. More than 97% of the senescent cells were excitatory neurons and overlapped with tau-containing neurofibrillary tangles (NFTs). 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 whereby p19-expressing neurons 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 phenotype. The eigengenes developed may be useful in future senescence profiling studies as they accurately identified senescent cells in snRNASeq datasets and predicted biomarkers for histological investigation.