Jara Claudia, Cerpa Waldo, Tapia-Rojas Cheril, Quintanilla Rodrigo A
Laboratory of Neurodegenerative Diseases, Universidad Autónoma de Chile, Santiago, Chile.
Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Santiago, Chile.
Front Neurosci. 2021 Feb 10;14:586710. doi: 10.3389/fnins.2020.586710. eCollection 2020.
Aging is an irreversible process and the primary risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial impairment is a process that generates oxidative damage and ATP deficit; both factors are important in the memory decline showed during normal aging and AD. Tau is a microtubule-associated protein, with a strong influence on both the morphology and physiology of neurons. In AD, tau protein undergoes post-translational modifications, which could play a relevant role in the onset and progression of this disease. Also, these abnormal forms of tau could be present during the physiological aging that could be related to memory impairment present during this stage. We previously showed that tau ablation improves mitochondrial function and cognitive abilities in young wild-type mice. However, the possible contribution of tau during aging that could predispose to the development of AD is unclear. Here, we show that tau deletion prevents cognitive impairment and improves mitochondrial function during normal aging as indicated by a reduction in oxidative damage and increased ATP production. Notably, we observed a decrease in cyclophilin-D (CypD) levels in aged tau-/- mice, resulting in increased calcium buffering and reduced mitochondrial permeability transition pore (mPTP) opening. The mPTP is a mitochondrial structure, whose opening is dependent on CypD expression, and new evidence suggests that this could play an essential role in the neurodegenerative process showed during AD. In contrast, hippocampal CypD overexpression in aged tau-/- mice impairs mitochondrial function evidenced by an ATP deficit, increased mPTP opening, and memory loss; all effects were observed in the AD pathology. Our results indicate that the absence of tau prevents age-associated cognitive impairment by maintaining mitochondrial function and reducing mPTP opening through a CypD-dependent mechanism. These findings are novel and represent an important advance in the study of how tau contributes to the cognitive and mitochondrial failure present during aging and AD in the brain.
衰老进程不可逆，是神经退行性疾病（如阿尔茨海默病，AD）发生发展的主要风险因素。线粒体损伤是一个产生氧化损伤和ATP缺乏的过程；这两个因素在正常衰老和AD过程中出现的记忆衰退中都很重要。Tau是一种微管相关蛋白，对神经元的形态和生理功能均有重大影响。在AD中，tau蛋白会发生翻译后修饰，这可能在该疾病的发生和发展中起重要作用。此外，这些异常形式的tau可能出现在生理衰老过程中，这可能与该阶段出现的记忆障碍有关。我们之前的研究表明，在年轻的野生型小鼠中，tau基因缺失可改善线粒体功能和认知能力。然而，tau在衰老过程中可能对AD的发生发展产生的影响尚不清楚。在此，我们发现tau基因缺失可预防正常衰老过程中的认知障碍，并改善线粒体功能，表现为氧化损伤减少和ATP生成增加。值得注意的是，我们观察到老年tau基因敲除小鼠中亲环蛋白D（CypD）水平降低，导致钙缓冲能力增强，线粒体通透性转换孔（mPTP）开放减少。mPTP是一种线粒体结构，其开放依赖于CypD的表达，新证据表明这可能在AD过程中出现的神经退行性变中起关键作用。相反，老年tau基因敲除小鼠海马区CypD过表达会损害线粒体功能，表现为ATP缺乏、mPTP开放增加和记忆丧失；这些效应均在AD病理过程中出现。我们的研究结果表明，tau基因缺失通过维持线粒体功能和通过依赖CypD的机制减少mPTP开放，预防了与年龄相关的认知障碍。这些发现具有创新性，代表了在研究tau如何导致大脑衰老和AD过程中出现的认知和线粒体功能障碍方面的重要进展。
