BMAL1 upregulates STX17 levels to promote autophagosome-lysosome fusion in hippocampal neurons to ameliorate Alzheimer’s disease

• Published in: iScience Vol. 27; no. 12; p. 111413
• Main Authors: Zhou, Xiuya, Du, Kaili, Mao, Tian, Wang, Ning, Zhang, Lifei, Tian, Yuan, Liu, Ting, Wang, Li, Wang, Xiaohui
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.12.2024; Elsevier
• Subjects: Cellular neuroscience; Molecular neuroscience; Neuroscience; Molecular neuroscience; Cellular neuroscience; Neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.111413

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. [Display omitted] •Reduced STX17 inhibits autophagy in hippocampal neurons, leading to Aβ accumulation•BMAL1 enhances STX17 transcription, facilitating SNARE complex and Aβ clearance•SNARE complex aids autophagy, clearing intracellular Aβ deposits•Circadian rhythm disruption in early AD stages increases Aβ deposition Neuroscience; Molecular neuroscience; Cellular neuroscience