BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease.

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.
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