Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Graduate Program in Biophysics and Harvard/MIT MD-PhD Program, Harvard University, Cambridge, MA 02139, USA.
Cell. 2023 Sep 28;186(20):4438-4453.e23. doi: 10.1016/j.cell.2023.08.005.
Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with β-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.
阿尔茨海默病（AD）的细胞扰动主要在人类死后样本和模式生物中进行研究。在这里，我们从一组来自患有不同程度 AD 病理的活体个体的皮质活检中生成了一个单细胞核图谱。接下来，我们进行了系统的跨疾病和跨物种综合分析，以确定一组特定于早期 AD 病理的细胞状态。这些变化——我们称之为早期皮质淀粉样蛋白反应——在神经元中很明显，我们通过对独立活检标本的急性切片生理学确认了兴奋性神经元丧失之前的过渡性过度活跃状态。过度表达神经炎症相关过程的小胶质细胞也随着 AD 病理的增加而扩张。最后，少突胶质细胞和锥体神经元在这个早期过度活跃阶段上调了与β-淀粉样蛋白产生和加工相关的基因。我们的综合分析为靶向 AD 发病机制早期的回路功能障碍、神经炎症和淀粉样蛋白产生提供了一个组织框架。
