Affiliations: [a] School of Medicine, Chongqing University, Chongqing, P.R. China
| [b] Department of Pathology, Chongqing University Cancer Hospital, Chongqing, P.R. China
| [c] Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer – iCQBC, Chongqing University Cancer Hospital, Chongqing, P.R. China
Correspondence:
[*]
Correspondence to: Yu Li, Department of Pathology, Chongqing University Cancer Hospital, Hanyu Road, Shapingba District, Chongqing, 400030, China. Tel.: +86 17760105474; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: Background:Mitochondrial dysfunction exists in Alzheimer’s disease (AD) brain, and damaged mitochondria need to be removed by mitophagy. Small GTPase Rab7 regulates the fusion of mitochondria and lysosome, while TBC1D5 inhibits Rab7 activation. However, it is not clear whether the regulation of Rab7 activity by TBC1D5 can improve mitophagy and inhibit AD progression. Objective:To investigate the role of TBC1D5 in mitophagy and its regulatory mechanism for Rab7, and whether activation of mitophagy can inhibit the progression of AD. Methods:Mitophagy was determined by western blot and immunofluorescence. The morphology and quantity of mitochondria were tracked by TEM. pCMV-Mito-AT1.03 was employed to detect the cellular ATP. Amyloid-β secreted by AD cells was detected by ELISA. Co-immunoprecipitation was used to investigate the binding partner of the target protein. Golgi-cox staining was applied to observe neuronal morphology of mice. The Morris water maze test and Y-maze were performed to assess spatial learning and memory, and the open field test was measured to evaluate motor function and anxiety-like phenotype of experimental animals. Results:Mitochondrial morphology was impaired in AD models, and TBC1D5 was highly expressed. Knocking down TBC1D5 increased the expression of active Rab7, promoted the fusion of lysosome and autophagosome, thus improving mitophagy, and improved the morphology of hippocampal neurons and the impaired behavior in AD mice. Conclusions:Knocking down TBC1D5 increased Rab7 activity and promoted the fusion of autophagosome and lysosome. Our study provided insights into the mechanisms that bring new possibilities for AD therapy targeting mitophagy.
