Microglial MHC-I induction with aging and Alzheimer's is conserved in mouse models and humans

Major Histocompatibility Complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses. Neuronal MHC-I has been proposed to regulate developmental synapse elimination and tau pathology in Alzheimer's disease (AD). Here we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia were the primary source of classical and non-classical MHC-I in mice and humans. Translating Ribosome Affinity Purification (TRAP)-qPCR analysis of 3-6 and 18-22 month old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 but not in astrocytes and neurons. Across a timecourse (12-23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was also enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I binding Leukocyte Immunoglobulin-like (Lilrs) and Paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell-autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in AD mouse models and human AD data is evident across numerous mouse models, methods, and studies. MHC-I expression correlated with p16INK4A, suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration. Overall design: RNA-Seq and qPCR of old and young mice to compare MHC-I expression with human data

主要组织相容性复合体I类（Major Histocompatibility Complex I, MHC-I）在中枢神经系统（Central Nervous System, CNS）的细胞定位与功能，此前曾被认为不存在于大脑中，至今仍未完全阐明。已有研究报道，在小鼠、大鼠及人类的全组织分析中，MHC-I的表达会随大脑衰老而上调。有研究提出，神经元MHC-I可调控阿尔茨海默病（Alzheimer's disease, AD）中的发育性突触消除与tau病理。
本研究通过分析新生成及公开可用的核糖体谱分析、细胞分选与单细胞测序数据，发现小胶质细胞是小鼠和人类体内经典与非经典MHC-I的主要来源。对3~6月龄和18~22月龄小鼠的翻译核糖体亲和纯化（Translating Ribosome Affinity Purification, TRAP）-qPCR分析显示，小胶质细胞中MHC-I通路基因B2m、H2-D1、H2-K1、H2-M3、H2-Q6及Tap1的表达随衰老显著上调，而星形胶质细胞和神经元中则无此变化。在12~23月龄的时间梯度实验中，小胶质细胞MHC-I表达逐渐升高，至21月龄后加速上升。MHC-I蛋白同样在小胶质细胞中富集，并随衰老增加。
小胶质细胞表达MHC-I结合受体家族——白细胞免疫球蛋白样受体（Leukocyte Immunoglobulin-like receptors, Lilrs）与配对免疫球蛋白样受体2型（Paired immunoglobin-like type 2 receptors, Pilrs），而星形胶质细胞和神经元则不表达这类受体，这可介导细胞自主性MHC-I信号通路，且这类受体的表达在小鼠和人类中均随衰老而上调。在阿尔茨海默病小鼠模型与人类AD数据中，均可观察到小胶质细胞MHC-I、Lilrs及Pilrs表达上调，这一现象在多种小鼠模型、实验方法与研究中均有体现。MHC-I的表达与p16INK4A相关，提示其与细胞衰老存在关联。
随着衰老与阿尔茨海默病过程中MHC-I、Lilrs及Pilrs的保守性上调，提示存在细胞自主性MHC-I信号通路，可调控衰老与神经退行性疾病中小胶质细胞的活化状态。总体实验设计：对老年与年轻小鼠开展RNA测序（RNA-Seq）与qPCR分析，以结合人类数据对比MHC-I的表达差异。