Okazawa Hitoshi
Department of Neuropathology, Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
Neuropathology. 2021 Apr;41(2):93-98. doi: 10.1111/neup.12738.
Using a new marker of necrosis, pSer46-MARCKS, which was identified by comprehensive phosphoproteome analysis as a phosphoprotein changed before appearance of extracellular amyloid aggregation, we discovered that neuronal necrosis occurs much earlier in Alzheimer's disease pathology than previously expected. The necrosis is induced by intracellular amyloid accumulation that deprives a critical effector molecule, Yes-associated protein (YAP), in the Hippo signaling pathway that is essential for cell survival, similarly to TRIAD necrosis observed in transcriptional repression and in other neurodegenerative diseases such as Huntington's disease. The initial TRIAD necrosis due to the intracellular amyloid releases HMGB1 into extracellular space and induces cluster of secondary necrosis around the primary necrotic neurons. Finally, the cluster grows into extracellular amyloid plaque. Inhibition of HMGB1 by anti-HMGB1 antibody prevents expansion of neurodegeneration. Administration even after onset significantly ameliorates the cognitive decline of Alzheimer's disease model mice. Our results present a new theory of Alzheimer's disease pathology, which can be referred to as the "intracellular amyloid hypothesis".
通过一种新的坏死标志物pSer46-MARCKS（这是通过全面的磷酸化蛋白质组分析鉴定出的一种在细胞外淀粉样蛋白聚集出现之前就发生变化的磷酸化蛋白），我们发现神经元坏死在阿尔茨海默病病理过程中发生的时间比之前预期的要早得多。这种坏死是由细胞内淀粉样蛋白积累诱导的，它剥夺了细胞存活所必需的Hippo信号通路中的关键效应分子Yes相关蛋白（YAP），这与在转录抑制以及其他神经退行性疾病（如亨廷顿舞蹈症）中观察到的TRIAD坏死类似。由于细胞内淀粉样蛋白导致的初始TRIAD坏死会将高迁移率族蛋白B1（HMGB1）释放到细胞外空间，并在原发性坏死神经元周围诱导继发性坏死聚集。最后，这种聚集发展成细胞外淀粉样斑块。用抗HMGB1抗体抑制HMGB1可防止神经退行性变的扩展。即使在发病后给药也能显著改善阿尔茨海默病模型小鼠的认知衰退。我们的研究结果提出了一种新的阿尔茨海默病病理理论，可称为“细胞内淀粉样蛋白假说”。
