Gazestani Vahid, Kamath Tushar, Nadaf Naeem M, Burris S J, Rooney Brendan, Junkkari Antti, Vanderburg Charles, Rauramaa Tuomas, Therrien Martine, Tegtmeyer Matthew, Herukka Sanna-Kaisa, Abdulraouf Abdulraouf, Marsh Samuel, Malm Tarja, Hiltunen Mikko, Nehme Ralda, Stevens Beth, Leinonen Ville, Macosko Evan Z
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.
bioRxiv. 2023 Jun 5:2023.06.03.543569. doi: 10.1101/2023.06.03.543569.
Cellular perturbations underlying Alzheimer's disease 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 Alzheimer's disease 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 transient state of hyperactivity preceding loss of excitatory neurons, which correlated with the selective loss of layer 1 inhibitory neurons. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathological burden increased. Lastly, both oligodendrocytes and pyramidal neurons upregulated genes associated with amyloid beta 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.
阿尔茨海默病潜在的细胞扰动主要在人类尸检样本和模式生物中进行研究。在此，我们从患有不同程度阿尔茨海默病病理的活体个体的罕见皮质活检队列中生成了一个单核图谱。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阿尔茨海默病病理的细胞状态。这些变化——我们称之为早期皮质淀粉样蛋白反应——在神经元中很突出，在其中我们确定了兴奋性神经元丧失之前的短暂过度活跃状态，这与第1层抑制性神经元的选择性丧失相关。随着阿尔茨海默病病理负担的增加，过度表达神经炎症相关过程的小胶质细胞也有所增加。最后，在这个早期过度活跃阶段，少突胶质细胞和锥体神经元都上调了与淀粉样β蛋白产生和加工相关的基因。我们的综合分析为在阿尔茨海默病发病机制早期针对回路功能障碍、神经炎症和淀粉样蛋白产生提供了一个组织框架。
