Molecular characterization of selectively vulnerable neurons in Alzheimer's Disease
Kun Leng, Emmy Li, Rana Eser, Antonia Piergies, Rene Sit, Michelle Tan, Norma Neff, Song Hua Li, Roberta Diehl Rodriguez, Claudia Kimie Suemoto, Renata Elaine Paraizo Leite, Alexander J. Ehrenberg, Carlos A. Pasqualucci, William W. Seeley, Salvatore Spina, Helmut Heinsen, Lea T. Grinberg, Martin Kampmann
Abstract
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.
Datasets
1. Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease: Superior frontal gyrus
2. Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease: Entorhinal Cortex
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Source data
https://cellxgene.cziscience.com/collections/180bff9c-c8a5-4539-b13b-ddbc00d643e6
Alias names
GSE147528, syn21788402, PMID33432193, PMC7854528
Cite this study
Leng, K., Li, E., Eser, R., Piergies, A., Sit, R., Tan, M., Neff, N., Li, S.H., Rodriguez, R.D., Suemoto, C.K. and Leite, R.E.P., 2021. Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nature neuroscience, 24(2), pp.276-287. https://doi.org/10.1038/s41593-020-00764-7