BMAL1 upregulates STX17 levels to promote autophagosome-lysosome fusion in hippocampal neurons to ameliorate Alzheimer’s disease
Xiuya Zhou,
Kaili Du,
Tian Mao,
Ning Wang,
Lifei Zhang,
Yuan Tian,
Ting Liu,
Li Wang,
Xiaohui Wang
Affiliations
Xiuya Zhou
Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, China; Department of Pathology, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
Kaili Du
Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, China; Department of Pathology, Shanxi Medical University, Taiyuan, China
Tian Mao
Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, China
Ning Wang
Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, China
Lifei Zhang
Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, China
Yuan Tian
Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, China
Ting Liu
Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, China; Department of Pathology, Shanxi Medical University, Taiyuan, China
Li Wang
Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, China; Department of Pathology, Shanxi Medical University, Taiyuan, China
Xiaohui Wang
Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China; Department of Pathology, Shanxi Medical University, Taiyuan, China; Corresponding author
Summary: We aim to investigate muscle ARNT-like protein 1 (BMAL1) regulation of syntaxin17 (STX17) in mouse hippocampal neurons, focusing on autophagy and amyloid-β (Aβ) deposition. Autophagosome-lysosome fusion in APP/PS1 hippocampal tissues was observed using transmission electron microscopy, while mRNA levels of LC3II and P62 were measured via reverse-transcription PCR (RT-PCR) after Amyloid precursor protein (APP) overexpression. STX17, linked to autophagy and differentially expressed in Alzheimer’s disease (AD) brains, was knocked down or overexpressed to assess its effects. The results showed that reduced STX17 impairs autophagosome-lysosome fusion, leading to abnormal Aβ deposition. Coimmunoprecipitation (Co-IP) and immunofluorescence confirmed STX17 interaction with SNAP29 and VAMP8 to form SNARE complexes. Furthermore, BMAL1 binding to STX17 was examined using luciferase assays. Circadian rhythm disturbances and decreased BMAL1 expression in APP/PS1 mice were noted, while BMAL1 overexpression upregulated STX17 expression and promoted autophagy to reduce Aβ deposition. Thus, the BMAL1 protein can promote STX17 transcription to induce STX17-SNAP29-VAMP8 complex formation to clear intracellular Aβ through autophagy.
