Maeda Jun, Minamihisamatsu Takeharu, Shimojo Masafumi, Zhou Xiaoyun, Ono Maiko, Matsuba Yukio, Ji Bin, Ishii Hideki, Ogawa Masanao, Akatsu Hiroyasu, Kaneda Daita, Hashizume Yoshio, Robinson John L, Lee Virginia M-Y, Saito Takashi, Saido Takaomi C, Trojanowski John Q, Zhang Ming-Rong, Suhara Tetsuya, Higuchi Makoto, Sahara Naruhiko
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan.
Brain Commun. 2021 Jan 29;3(1):fcab011. doi: 10.1093/braincomms/fcab011. eCollection 2021.
Microglia are the resident phagocytes of the central nervous system, and microglial activation is considered to play an important role in the pathogenesis of neurodegenerative diseases. Recent studies with single-cell RNA analysis of CNS cells in Alzheimer's disease and diverse other neurodegenerative conditions revealed that the transition from homeostatic microglia to disease-associated microglia was defined by changes of gene expression levels, including down-regulation of the P2Y12 receptor gene (). However, it is yet to be clarified in Alzheimer's disease brains whether and when this down-regulation occurs in response to amyloid-β and tau depositions, which are core pathological processes in the disease etiology. To further evaluate the significance of P2Y12 receptor alterations in the neurodegenerative pathway of Alzheimer's disease and allied disorders, we generated an anti-P2Y12 receptor antibody and examined P2Y12 receptor expressions in the brains of humans and model mice bearing amyloid-β and tau pathologies. We observed that the brains of both Alzheimer's disease and non-Alzheimer's disease tauopathy patients and tauopathy model mice (rTg4510 and PS19 mouse lines) displayed declined microglial P2Y12 receptor levels in regions enriched with tau inclusions, despite an increase in the total microglial population. Notably, diminution of microglial immunoreactivity with P2Y12 receptor was noticeable prior to massive accumulations of phosphorylated tau aggregates and neurodegeneration in rTg4510 mouse brains, despite a progressive increase of total microglial population. On the other hand, Iba1-positive microglia encompassing compact and dense-cored amyloid-β plaques expressed P2Y12 receptor at varying levels in amyloid precursor protein (APP) mouse models (APP23 and mice). By contrast, neuritic plaques in Alzheimer's disease brains were associated with P2Y12 receptor-negative microglia. These data suggest that the down-regulation of microglia P2Y12 receptor, which is characteristic of disease-associated microglia, is intimately associated with tau rather than amyloid-β pathologies from an early stage and could be a sensitive index for neuroinflammatory responses to Alzheimer's disease-related neurodegenerative processes.
小胶质细胞是中枢神经系统中的常驻吞噬细胞，小胶质细胞激活被认为在神经退行性疾病的发病机制中起重要作用。最近对阿尔茨海默病及其他多种神经退行性疾病的中枢神经系统细胞进行单细胞RNA分析的研究表明，从稳态小胶质细胞向疾病相关小胶质细胞的转变是由基因表达水平的变化所定义的，包括P2Y12受体基因的下调（）。然而，在阿尔茨海默病大脑中，这种下调是否以及何时因淀粉样β蛋白和tau蛋白沉积（疾病病因中的核心病理过程）而发生，仍有待阐明。为了进一步评估P2Y12受体改变在阿尔茨海默病及相关疾病神经退行性通路中的意义，我们制备了一种抗P2Y12受体抗体，并检测了患有淀粉样β蛋白和tau蛋白病变的人类和模型小鼠大脑中P2Y12受体的表达。我们观察到，阿尔茨海默病患者和非阿尔茨海默病tau蛋白病患者以及tau蛋白病模型小鼠（rTg4510和PS19小鼠品系）的大脑在富含tau蛋白包涵体的区域中，尽管小胶质细胞总数增加，但小胶质细胞P2Y12受体水平下降。值得注意的是，在rTg4510小鼠大脑中，尽管小胶质细胞总数逐渐增加，但在磷酸化tau蛋白聚集体大量积累和神经退行性变之前，小胶质细胞与P2Y12受体的免疫反应性明显降低。另一方面，在淀粉样前体蛋白（APP）小鼠模型（APP23和小鼠）中，包围紧密和致密核心淀粉样β蛋白斑块的Iba1阳性小胶质细胞表达不同水平的P2Y12受体。相比之下，阿尔茨海默病大脑中的神经炎性斑块与P2Y12受体阴性的小胶质细胞相关。这些数据表明，小胶质细胞P2Y12受体的下调是疾病相关小胶质细胞的特征，从早期就与tau蛋白病变而非淀粉样β蛋白病变密切相关，并且可能是对阿尔茨海默病相关神经退行性过程神经炎症反应的敏感指标
