Molecular Characterization of Selectively Vulnerable Neurons in Alzheimer’S Disease
RESOURCE https://doi.org/10.1038/s41593-020-00764-7 Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease Kun Leng1,2,3,4,13, Emmy Li1,2,3,13, Rana Eser 5, Antonia Piergies5, Rene Sit2, Michelle Tan2, Norma Neff 2, Song Hua Li5, Roberta Diehl Rodriguez6, Claudia Kimie Suemoto7,8, Renata Elaine Paraizo Leite7, Alexander J. Ehrenberg 5, Carlos A. Pasqualucci7, William W. Seeley5,9, Salvatore Spina5, Helmut Heinsen7,10, Lea T. Grinberg 5,7,11 ✉ and Martin Kampmann 1,2,12 ✉ Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular sig- natures 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 neu- rons 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. elective vulnerability is a fundamental feature of neurodegen- Here, we performed snRNA-seq on postmortem brain tissue erative diseases, in which different neuronal populations show from a cohort of individuals spanning the progression of AD-type a gradient of susceptibility to degeneration.
[Show full text]