Tomaru Utano, Ito Tomoki, Ohmura Yu, Higashikawa Kei, Miyajima Syota, Tomatsu Ruka, Higashi Tsunehito, Ishizu Akihiro, Kuge Yuji, Yoshioka Mitsuhiro, Kasahara Masanori
Department of Pathology, Hokkaido University, Sapporo, Japan.
Department of Pathology, Hokkaido University, Sapporo, Japan.
Am J Pathol. 2021 Jan;191(1):144-156. doi: 10.1016/j.ajpath.2020.10.004.
Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia worldwide. There is considerable evidence of age-related disruption of proteostasis being responsible for the development of AD. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and an age-related decline in its activity has been implicated in age-related pathologies. Although proteasomal dysfunction is assumed to be a key AD hallmark, it remains unclear whether its role in disease onset is causative or secondary. In this study, we demonstrate that mice with proteasomal dysfunction exhibited memory impairment with associated neuronal loss, accumulation of phosphorylated tau, and activation of endoplasmic reticulum (ER) stress-related apoptosis pathways. Impaired proteasomal activity also activated ER stress-related apoptosis pathways in HT-22, a murine hippocampal neuronal cell line. HT-22 cell death, caused by proteasomal inhibition, was prevented by an inhibitor of c-Jun N-terminal kinase, an ER stress-related molecule. Collective evidence suggests that impaired proteasomal activity alters proteostasis, and subsequent ER stress-mediated pathways play pivotal roles in neuronal loss. Because aging decreases proteasomal function, age-related impairment of proteasomes may be involved in the development and progression of AD in elderly patients.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，也是全球最常见的痴呆类型。有大量证据表明，与年龄相关的蛋白质稳态破坏是AD发病的原因。蛋白酶体是一种多催化酶复合物，可降解正常和受损蛋白质，其活性随年龄增长而下降与年龄相关的病理变化有关。尽管蛋白酶体功能障碍被认为是AD的一个关键标志，但其在疾病发病中的作用是因果性的还是继发性的仍不清楚。在本研究中，我们证明蛋白酶体功能障碍的小鼠表现出记忆障碍，并伴有神经元丢失、磷酸化tau蛋白的积累以及内质网（ER）应激相关凋亡途径的激活。蛋白酶体活性受损还激活了小鼠海马神经元细胞系HT-22中的ER应激相关凋亡途径。蛋白酶体抑制导致的HT-22细胞死亡可被c-Jun氨基末端激酶（一种ER应激相关分子）的抑制剂所阻止。综合证据表明，蛋白酶体活性受损会改变蛋白质稳态，随后ER应激介导的途径在神经元丢失中起关键作用。由于衰老会降低蛋白酶体功能，蛋白酶体与年龄相关的损伤可能参与老年患者AD的发生和发展。
