Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Chiome Bioscience, Inc., Sumitomo Fudosan Nishi-shinjuku Building No. 6, 3-12-1 Honmachi, Shibuya-ku, Tokyo, 151-0071, Japan.
Commun Biol. 2021 Oct 11;4(1):1175. doi: 10.1038/s42003-021-02671-4.
DNA damage is increased in Alzheimer's disease (AD), while the underlying mechanisms are unknown. Here, we employ comprehensive phosphoproteome analysis, and identify abnormal phosphorylation of 70 kDa subunit of Ku antigen (Ku70) at Ser77/78, which prevents Ku70-DNA interaction, in human AD postmortem brains. The abnormal phosphorylation inhibits accumulation of Ku70 to the foci of DNA double strand break (DSB), impairs DNA damage repair and eventually causes transcriptional repression-induced atypical cell death (TRIAD). Cells under TRIAD necrosis reveal senescence phenotypes. Extracellular high mobility group box 1 (HMGB1) protein, which is released from necrotic or hyper-activated neurons in AD, binds to toll-like receptor 4 (TLR4) of neighboring neurons, and activates protein kinase C alpha (PKCα) that executes Ku70 phosphorylation at Ser77/78. Administration of human monoclonal anti-HMGB1 antibody to post-symptomatic AD model mice decreases neuronal DSBs, suppresses secondary TRIAD necrosis of neurons, prevents escalation of neurodegeneration, and ameliorates cognitive symptoms. TRIAD shares multiple features with senescence. These results discover the HMGB1-Ku70 axis that accounts for the increase of neuronal DNA damage and secondary enhancement of TRIAD, the cell death phenotype of senescence, in AD.
DNA 损伤在阿尔茨海默病（AD）中增加，而潜在的机制尚不清楚。在这里，我们采用综合磷酸化组学分析方法，在人类 AD 尸检大脑中发现了 Ku 抗原 70kDa 亚基（Ku70）在丝氨酸 77/78 处异常磷酸化，这阻止了 Ku70-DNA 相互作用。异常磷酸化抑制 Ku70 积累到 DNA 双链断裂（DSB）的焦点，损害 DNA 损伤修复，最终导致转录抑制诱导的非典型细胞死亡（TRIAD）。处于 TRIAD 坏死状态的细胞表现出衰老表型。AD 中坏死或过度激活神经元释放的细胞外高迁移率族蛋白 1（HMGB1）与邻近神经元的 Toll 样受体 4（TLR4）结合，并激活蛋白激酶 Cα（PKCα），使 Ku70 在丝氨酸 77/78 处发生磷酸化。向 AD 后发病模型小鼠施用人源单克隆抗 HMGB1 抗体可减少神经元 DSB，抑制神经元继发性 TRIAD 坏死，阻止神经退行性变的加剧，并改善认知症状。TRIAD 与衰老具有多个共同特征。这些结果发现了 HMGB1-Ku70 轴，该轴解释了 AD 中神经元 DNA 损伤的增加和继发性 TRIAD 的增强，即衰老的细胞死亡表型。
