美国加州大学Martin Kampmann和Lea T. Grinberg研究团队合作揭示阿尔茨海默氏病（AD）中选择性脆弱神经元的分子表征。该项研究成果发表在2021年出1月11日版的《自然-神经科学》杂志上。

为了鉴定和表征选择性脆弱的神经元群体，他们使用单核RNA测序对尾部的内嗅皮层和上额回（大脑区域，分别在AD的早期和晚期出现神经原纤维包涵体和神经元丢失）进行了分布分析，这些包括了从死亡大脑跨越AD型tau神经原纤维的病理学进展。他们将RORB确定为内嗅皮层中选择性脆弱的兴奋性神经元标志物，随后使用定量神经病理学方法验证了它们在疾病进展过程中的耗竭和对神经原纤维包涵体的选择性敏感性。

他们还发现了星形胶质细胞亚群，可能代表反应性星形胶质细胞，其特征是参与稳态功能的基因表达降低。他们对AD中选择性脆弱神经元的表征，为将来的选择性脆弱性机理研究和增强神经元适应能力的潜在治疗策略铺平了道路。

据悉，AD的特征是特定神经元群体的选择性脆弱性，其分子特征在很大程度上尚不清楚。

附：英文原文

Title: Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease

Author: 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

Issue&Volume: 2021-01-11

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.

DOI: 10.1038/s41593-020-00764-7

Source: https://www.nature.com/articles/s41593-020-00764-7