The neuropathological hallmarks of Alzheimer's Disease are plaques and neurofibrillary tangles. Yet, Alzheimer's is a complex disease with many contributing factors, such as energy-metabolic changes, which have been documented in autopsy brains from individuals with Alzheimer's and animal disease models alike. One conceivable explanation is that the interplay of age-related extracellular and intracellular alterations pertaining to Alzheimer's, such as cerebrovascular changes, protein aggregates and inflammation, evoke a mitochondrial response. However, it is not clear if and how mitochondria can contribute to Alzheimer's pathophysiology. This study focuses on one particular aspect of this question by investigating the functional interaction between the microtubule-associated protein tau and the mitochondrial inner membrane fusion machinery, which shows alterations in Alzheimer's brains. OPA1 is an essential inner membrane-fusion protein regulated by the two membrane proteases OMA1 and YME1L1. Assessment of OPA1 proteolysis—usually found in dividing mitochondria—and posttranslational tau modifications in mouse and human neuroblastoma cells under different experimental conditions clarified the relationship between these two pathways: OPA1 hydrolysis and phosphorylation or dephosphorylation of tau may coincide, but are not causally related. OPA1 cleavage did not alter tau's phosphorylation pattern. Conversely, tau's phosphorylation state did not induce nor correlate with OPA1 proteolysis. These results irrefutably demonstrate that there is no direct functional interaction between posttranslational tau modifications and the regulation of the OMA1-OPA1 pathway, which implies a common root cause modulating both pathways in Alzheimer's.

阿尔茨海默病的神经病理学特征是斑块和神经原纤维缠结。然而，阿尔茨海默氏症是一种复杂的疾病，有许多影响因素，例如能量代谢的变化，这些变化已在阿尔茨海默氏症患者和动物疾病模型的尸检大脑中得到记录。一种可能的解释是，与阿尔茨海默病有关的与年龄相关的细胞外和细胞内改变（例如脑血管变化、蛋白质聚集和炎症）相互作用，引起线粒体反应。然而，目前尚不清楚线粒体是否以及如何促进阿尔茨海默病的病理生理学。这项研究通过研究微管相关蛋白 tau 和线粒体内膜融合机制之间的功能相互作用来关注这一问题的一个特定方面，该机制显示了阿尔茨海默病大脑中的变化。OPA1 是一种重要的内膜融合蛋白，受两种膜蛋白酶 OMA1 和 YME1L1 调节。在不同实验条件下对小鼠和人类神经母细胞瘤细胞中 OPA1 蛋白水解作用（通常存在于分裂线粒体中）和翻译后 tau 修饰进行评估，阐明了这两种途径之间的关系：OPA1 水解和 tau 磷酸化或去磷酸化可能同时发生，但并不存在因果关系。OPA1 裂解不会改变 tau 蛋白的磷酸化模式。相反，tau 的磷酸化状态不会诱导 OPA1 蛋白水解，也不会与 OPA1 蛋白水解相关。这些结果无可辩驳地证明，翻译后 tau 修饰与 OMA1-OPA1 通路的调节之间不存在直接的功能相互作用，这意味着在阿尔茨海默病中调节这两种通路有一个共同的根本原因。