Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease. Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease

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. The brain tissue used in this study were sourced from the Biobank for Aging Studies (LIM-22) in the Department of Pathology at the University of Sao Paulo, as well as from the Neurodegenerative Diseases Brain Bank in the Memory and Aging Center at the University of California, San Francisco. Detailed neuropathological, clinical and genetic data are available under request. Please contact [e-mail] and [e-mail]. Overall design: Single-nucleus RNA-sequencing of post-mortem brain tissue from donors spanning the range of AD progression.

阿尔茨海默病（Alzheimer’s disease, AD）以特定神经元群体的选择性易损性为特征，但其分子特征在很大程度上仍未被明确。为鉴定并表征具有选择性易损性的神经元群体，我们对覆盖阿尔茨海默病神经病理进展全阶段的供体样本，采用单细胞核RNA测序（single-nucleus RNA sequencing）技术对两个脑区进行了转录组分析：分别为AD发病早期出现神经纤维缠结（neurofibrillary inclusions）与神经元丢失的尾侧内嗅皮层（caudal entorhinal cortex），以及AD发病晚期出现此类病变的额上回（superior frontal gyrus）。我们鉴定出RORB可作为尾侧内嗅皮层内选择性易损性兴奋性神经元的标记物，并随后通过定量神经病理学方法，验证了该类神经元在疾病进程中的缺失现象及其对神经纤维缠结的选择性易感性。我们还发现了一类星形胶质细胞亚群，其特征为稳态功能相关基因的表达下调，该亚群大概率为反应性星形胶质细胞（reactive astrocytes）。本研究对阿尔茨海默病中选择性易损神经元的表征，为探索选择性易损性的潜在机制以及提升神经元抗损伤能力的潜在治疗策略铺平了道路。本研究使用的脑组织样本来源于圣保罗大学病理学系衰老研究生物样本库（LIM-22），以及加州大学旧金山分校记忆与衰老中心神经退行性疾病脑库。详细的神经病理学、临床及遗传学数据可按需获取，联系方式为[e-mail]与[e-mail]。研究总体设计：对覆盖阿尔茨海默病进展全阶段的遗体捐献者脑组织样本开展单细胞核RNA测序。