Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder. A defining hallmark of the AD brain is the presence of intraneuronal neurofibrillary tangles (NFTs) which are made up of abnormally modified tau, with aberrant phosphorylation being the most studied posttranslational modification (PTM). Although the accumulation of tau as NFTs is an invariant feature of the AD brain, it has become evident that these insoluble aggregates are likely not the primary pathogenic form of tau, rather soluble forms of tau with abnormal PTMs are the mediators of toxicity. The most prevalent PTM on tau is phosphorylation, with the abnormal modification of specific residues on tau playing a key role in its toxicity. Even though it is widely accepted that tau with aberrant PTMs facilitates neurodegeneration, the precise cellular mechanisms remain unknown. Nonetheless, there is an evolving conceptual framework that an important contributing factor may be selective pathological tau species compromising mitochondrial biology. Understanding the mechanisms by which tau with site-specific PTM impacts mitochondria is crucial for understanding the role tau plays in AD. Here, we provide a brief introduction to tau and its phosphorylation and function in a physiological context, followed by a discussion of the impact of soluble phosphorylated tau species on neuronal processes in general and mitochondria more specifically. We also discuss how therapeutic strategies that attenuate pathological tau species in combination with treatments that improve mitochondrial biology could be a potential therapeutic avenue to mitigate disease progression in AD and other tauopathies.

阿尔茨海默病 (AD) 是最常见的进行性神经退行性疾病。AD 大脑的一个明确标志是存在由异常修饰的 tau 组成的神经元内神经原纤维缠结 (NFT)，其中异常磷酸化是研究最多的翻译后修饰 (PTM)。尽管 tau 作为 NFT 的积累是 AD 大脑的一个不变特征，但很明显，这些不溶性聚集体可能不是 tau 的主要致病形式，而是具有异常 PTM 的可溶性 tau 形式是毒性的介质。tau 上最普遍的 PTM 是磷酸化，tau 上特定残基的异常修饰在其毒性中起关键作用。尽管人们普遍认为带有异常 PTM 的 tau 会促进神经变性，确切的细胞机制仍然未知。尽管如此，有一个不断发展的概念框架，一个重要的促成因素可能是损害线粒体生物学的选择性病理性 tau 物种。了解具有位点特异性 PTM 的 tau 影响线粒体的机制对于了解 tau 在 AD 中的作用至关重要。在这里，我们简要介绍了 tau 及其在生理环境中的磷酸化和功能，然后讨论了可溶性磷酸化 tau 物种对一般神经元过程和线粒体的影响。