RT Journal Article SR Electronic T1 Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.04.04.025825 DO 10.1101/2020.04.04.025825 A1 Kun Leng A1 Emmy Li A1 Rana Eser A1 Antonia Piergies A1 Rene Sit A1 Michelle Tan A1 Norma Neff A1 Song Hua Li A1 Roberta Diehl Rodriguez A1 Claudia Kimie Suemoto A1 Renata Elaine Paraizo Leite A1 Carlos A. Pasqualucci A1 William W. Seeley A1 Salvatore Spina A1 Helmut Heinsen A1 Lea T. Grinberg A1 Martin Kampmann YR 2020 UL http://biorxiv.org/content/early/2020/04/05/2020.04.04.025825.1.abstract AB 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 individuals spanning the neuropathological progression of AD. 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.