Yamakawa Mai, Rexach Jessica E
Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, USA.
Biomedicines. 2024 Jan 29;12(2):308. doi: 10.3390/biomedicines12020308.
Alzheimer's disease (AD) is a multi-stage neurodegenerative disorder characterized by beta-amyloid accumulation, hyperphosphorylated Tau deposits, neurodegeneration, neuroinflammation, and cognitive impairment. Recent studies implicate CD8 T cells as neuroimmune responders to the accumulation of AD pathology in the brain and potential contributors to toxic neuroinflammation. However, more evidence is needed to understand lymphocytes in disease, including their functional states, molecular mediators, and interacting cell types in diseased brain tissue. The scarcity of lymphocytes in brain tissue samples has limited the unbiased profiling of disease-associated cell types, cell states, drug targets, and relationships to common AD genetic risk variants based on transcriptomic analyses. However, using recent large-scale, high-quality single-nuclear sequencing datasets from over 84 Alzheimer's disease and control cases, we leverage single-nuclear RNAseq data from 800 lymphocytes collected from 70 individuals to complete unbiased molecular profiling. We demonstrate that effector memory CD8 T cells are the major lymphocyte subclass enriched in the brain tissues of individuals with AD dementia. We define disease-enriched interactions involving CD8 T cells and multiple brain cell subclasses including two distinct microglial disease states that correlate, respectively, to beta-amyloid and tau pathology. We find that beta-amyloid-associated microglia are a major hub of multicellular cross-talk gained in disease, including interactions involving both vulnerable neuronal subtypes and CD8 T cells. We reproduce prior reports that amyloid-response microglia are depleted in carriers. Overall, these human-based studies provide additional support for the potential relevance of effector memory CD8 T cells as a lymphocyte population of interest in AD dementia and provide new candidate interacting partners and drug targets for further functional study.
阿尔茨海默病（AD）是一种多阶段神经退行性疾病，其特征为β-淀粉样蛋白积累、tau蛋白过度磷酸化沉积、神经退行性变、神经炎症和认知障碍。最近的研究表明，CD8 T细胞是对大脑中AD病理积累产生神经免疫反应的细胞，也是有毒神经炎症的潜在促成因素。然而，需要更多证据来了解疾病中的淋巴细胞，包括它们的功能状态、分子介质以及患病脑组织中的相互作用细胞类型。脑组织样本中淋巴细胞的稀缺限制了基于转录组分析对疾病相关细胞类型、细胞状态、药物靶点以及与常见AD遗传风险变异之间关系的无偏分析。然而，利用最近来自84例以上阿尔茨海默病患者和对照病例的大规模、高质量单核测序数据集，我们利用从70名个体收集的800个淋巴细胞的单核RNA测序数据完成了无偏分子分析。我们证明，效应记忆CD8 T细胞是AD痴呆患者脑组织中富集的主要淋巴细胞亚类。我们定义了涉及CD8 T细胞和多种脑细胞亚类的疾病富集相互作用，包括两种分别与β-淀粉样蛋白和tau病理相关的不同小胶质细胞疾病状态。我们发现，与β-淀粉样蛋白相关的小胶质细胞是疾病中多细胞相互作用的主要枢纽，包括涉及脆弱神经元亚型和CD8 T细胞的相互作用。我们重现了之前的报道，即淀粉样蛋白反应性小胶质细胞在携带者中减少。总体而言，这些基于人类的研究为效应记忆CD8 T细胞作为AD痴呆中有研究价值的淋巴细胞群体的潜在相关性提供了额外支持，并为进一步的功能研究提供了新的候选相互作用伙伴和药物靶点。
