2. Academic Validation
  3. BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease

BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease

  • Brain. 2024 Jul 25:awae241. doi: 10.1093/brain/awae241.
Yang Yang 1 2,  Hui Chen 3,  Shuwen Huang 2,  Hao Chen 2,  Alexei Verkhratsky 4 5 6 7,  Jianqin Niu 8 9,  Yibo Qu 2,  Chenju Yi 1 10 11
Affiliations

Affiliations

  • 1 Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.
  • 2 Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.
  • 3 School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia.
  • 4 Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK.
  • 5 Achucarro Center for Neuroscience, IKERBASQUE, Bilbao, 48011, Spain.
  • 6 Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, Vilnius, 01102, Lithuania.
  • 7 Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, 110122, China.
  • 8 Department of Histology and Embryology, Third Military Medical University, Chongqing, 400038, China.
  • 9 Chongqing Key Laboratory of Neurobiology, Chongqing, 400038, China.
  • 10 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, 50630, China.
  • 11 Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, Shenzhen 518107, China.
PMID: 39054908 DOI: 10.1093/brain/awae241
Abstract

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 (AD). Promoting Mitophagy has been shown to improve cognitive function in AD 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 AD patients 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 AD-related changes. Our findings uncover a novel mechanism of BOK signaling through regulating Parkin-mediated Mitophagy to mitigate amyloid pathology, mitochondrial and synaptic malfunctions, and cognitive decline in AD, thus representing a promising therapeutic target.

Keywords

amyloid-β; cognitive decline; mitochondrial dysfunction; mitophagy; synaptophysin loss.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-D0985A
    98.70%, Mitochondrial Membrane Potential Fluorescent Dye