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Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease

By Kun Leng, Emmy Li, Rana Eser, Antonia Piergies, Rene Sit, Michelle Tan, Norma F. Neff, Song Hua Li, Roberta Diehl Rodriguez, Claudia Kimie Suemoto, Renata Elaine Paraizo Leite, Carlos A Pasqualucci, William W Seeley, Salvatore Spina, Helmut Heinsen, Lea Grinberg, Martin Kampmann

Posted 05 Apr 2020
bioRxiv DOI: 10.1101/2020.04.04.025825

Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience. ### Competing Interest Statement The authors have declared no competing interest.

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