Edmond & Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Center for Translational & Computational Immunology, Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
Nat Neurosci. 2023 Jul;26(7):1267-1280. doi: 10.1038/s41593-023-01356-x. Epub 2023 Jun 19.
The role of different cell types and their interactions in Alzheimer's disease (AD) is a complex and open question. Here, we pursued this question by assembling a high-resolution cellular map of the aging frontal cortex using single-nucleus RNA sequencing of 24 individuals with a range of clinicopathologic characteristics. We used this map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA sequencing, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including a somatostatin inhibitory neuronal subtype and oligodendroglial states. We further identified a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and we found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia.
不同细胞类型及其相互作用在阿尔茨海默病（AD）中的作用是一个复杂且尚未解决的问题。在这里，我们通过对 24 名具有不同临床病理特征的个体进行单细胞 RNA 测序，构建了一个高分辨率的衰老额皮质细胞图谱，以探索这个问题。我们使用这个图谱推断了 638 名通过 bulk RNA 测序进行分析的个体的新皮质细胞结构，为识别具有统计学意义的可靠关联提供了必要的样本量。我们发现了与 AD 相关的多种细胞群体，包括生长抑素抑制性神经元亚型和少突胶质细胞状态。我们进一步鉴定了一个由多细胞群落组成的网络，每个群落由神经元、神经胶质和内皮细胞的协调亚群组成，我们发现这两个群落在 AD 中发生了改变。最后，我们使用中介分析来确定可能导致认知能力下降的细胞变化。因此，我们对衰老新皮质的解构为评估 AD 和痴呆症的细胞微环境提供了路线图。
