Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Int J Mol Sci. 2024 Nov 17;25(22):12335. doi: 10.3390/ijms252212335.
In Alzheimer's disease (AD), tau dissociates from microtubules (MTs) due to hyperphosphorylation and misfolding. It is degraded by various mechanisms, including the 20S proteasome, chaperone-mediated autophagy (CMA), 26S proteasome, macroautophagy, and aggrephagy. Neurofibrillary tangles (NFTs) form upon the impairment of aggrephagy, and eventually, the ubiquitin chaperone valosin-containing protein (VCP) and heat shock 70 kDa protein (HSP70) are recruited to the sites of NFTs for the extraction of tau for the ubiquitin-proteasome system (UPS)-mediated degradation. However, the impairment of tau degradation in neurons allows tau to be secreted into the extracellular space. Secreted tau can be monomers, oligomers, and paired helical filaments (PHFs), which are seeding competent pathological tau that can be endocytosed/phagocytosed by healthy neurons, microglia, astrocytes, oligodendrocyte progenitor cells (OPCs), and oligodendrocytes, often causing proteotoxic stress and eventually triggers senescence. Senescent cells secrete various senescence-associated secretory phenotype (SASP) factors, which trigger cellular atrophy, causing decreased brain volume in human AD. However, the molecular mechanisms of proteotoxic stress and cellular senescence are not entirely understood and are an emerging area of research. Therefore, this comprehensive review summarizes pertinent studies that provided evidence for the sequential tau degradation, failure, and the mechanistic link between tau-driven proteotoxic stress and cellular senescence in AD.
在阿尔茨海默病（AD）中，由于过度磷酸化和错误折叠，tau 从微管（MT）中解离。它通过各种机制降解，包括 20S 蛋白酶体、伴侣介导的自噬（CMA）、26S 蛋白酶体、巨自噬和聚集体自噬。在聚集体自噬受损后形成神经原纤维缠结（NFT），最终泛素衔接蛋白 valosin 包含蛋白（VCP）和热休克 70 kDa 蛋白（HSP70）被募集到 NFT 部位，提取 tau 进行泛素蛋白酶体系统（UPS）介导的降解。然而，神经元中 tau 降解的受损允许 tau 被分泌到细胞外空间。分泌的 tau 可以是单体、寡聚物和双螺旋丝（PHF），它们是具有成核能力的病理性 tau，可被健康神经元、小胶质细胞、星形胶质细胞、少突胶质细胞前体细胞（OPC）和少突胶质细胞内吞/吞噬，通常导致蛋白毒性应激，最终引发衰老。衰老细胞分泌各种衰老相关分泌表型（SASP）因子，触发细胞萎缩，导致人类 AD 大脑体积减少。然而，蛋白毒性应激和细胞衰老的分子机制尚不完全清楚，这是一个新兴的研究领域。因此，这篇综述总结了相关研究，为 AD 中 tau 驱动的蛋白毒性应激和细胞衰老之间的连续 tau 降解、失效和机制联系提供了证据。
