Mitochondrial malfunction associated with impaired mitochondrial quality control and self-renewal machinery, known as mitophagy, is an under-appreciated mechanism precipitating synaptic loss and cognitive impairments in Alzheimer’s disease. Promoting mitophagy has been shown to improve cognitive function in Alzheimer’s disease animals. However, the regulatory mechanism was unclear, which formed the aim of this study. Here, we found that a neuron-specific loss of Bcl-2 family member BOK in patients with Alzheimer’s disease and APPswe/PS1dE9 (APP/PS1) mice is closely associated with mitochondrial damage and mitophagy defects. We further revealed that BOK is the key to the Parkin-mediated mitophagy through competitive binding to the MCL1/Parkin complex, resulting in Parkin release and translocation to damaged mitochondria to initiate mitophagy. Furthermore, overexpressing bok in hippocampal neurons of APP/PS1 mice alleviated mitophagy and mitochondrial malfunction, resulting in improved cognitive function. Conversely, the knockdown of bok worsened the aforementioned Alzheimer’s disease-related changes. Our findings uncover a novel mechanism of BOK signalling through regulating Parkin-mediated mitophagy to mitigate amyloid pathology, mitochondrial and synaptic malfunctions, and cognitive decline in Alzheimer’s disease, thus representing a promising therapeutic target.

中文翻译：

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BOK 参与的线粒体自噬缓解阿尔茨海默病的神经病理学


与线粒体质量控制和自我更新机制受损相关的线粒体功能障碍（称为线粒体自噬）是阿尔茨海默病中导致突触丢失和认知障碍的一种未被充分认识的机制。促进线粒体自噬已被证明可以改善阿尔茨海默病动物的认知功能。然而，调节机制尚不清楚，这构成了本研究的目的。在这里，我们发现阿尔茨海默病患者和 APPswe/PS1dE9 （APP/PS1） 小鼠 Bcl-2 家族成员 BOK 的神经元特异性缺失与线粒体损伤和线粒体自噬缺陷密切相关。我们进一步揭示，BOK 是通过与 MCL1/Parkin 复合物竞争性结合，是 Parkin 介导的线粒体自噬的关键，导致 Parkin 释放并易位到受损的线粒体以启动线粒体自噬。此外，在 APP/PS1 小鼠的海马神经元中过表达 bok 减轻了线粒体自噬和线粒体功能障碍，从而改善了认知功能。相反，bok 的敲除加剧了上述阿尔茨海默病相关变化。我们的研究结果揭示了 BOK 信号传导通过调节 Parkin 介导的线粒体自噬来减轻阿尔茨海默病中的淀粉样蛋白病理、线粒体和突触功能障碍以及认知能力下降的新机制，因此代表了一个有前途的治疗靶点。