Targeting Aβ and p-Tau Clearance in Methamphetamine-Induced Alzheimer's Disease-Like Pathology: Roles of Syntaxin 17 in Autophagic Degradation in Primary Hippocampal Neurons.

Abstract

Methamphetamine (Meth), a central nervous system (CNS) stimulant with strong neurotoxicity, causes progressive cognitive impairment with characterized neurodegenerative changes. However, the mechanism underlying Meth-induced pathological changes remains poorly understood. In the current study, Meth elicited a striking accumulation of the pathological proteins hyperphosphorylated tau (p-tau) and amyloid beta (Aβ) in primary hippocampal neurons, while the activation of autophagy dramatically ameliorated the high levels of these pathological proteins. Interestingly, after the Meth treatment, Aβ was massively deposited in autophagosomes, which were remarkably trapped in early endosomes. Mechanistically, syntaxin 17 (Stx17), a key soluble n-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor (SNARE) protein responsible for autophagosome and mature endosome/lysosome fusion, was significantly downregulated and hindered in combination with autophagosomes. Notably, adenovirus overexpression of Stx17 in primary neurons facilitated autophagosome-mature endosome/lysosome fusion, which dramatically reversed the Meth-induced increases in the levels of p-tau, Aβ, beta-secretase (Bace-1), and C-terminal fragments (CTFs). Immunofluorescence assays showed that Stx17 retarded the Meth-induced Aβ, p-tau, and Bace-1 accumulation in autophagosomes and facilitated the translocation of these pathological proteins to lysosomes, which indicated the importance of Stx17 via enhanced autophagosome-mature endosome/lysosome fusion. Therefore, the current study reveals a novel mechanism involving Meth-induced high levels of pathological proteins in neurons. Targeting Stx17 may provide a novel therapeutic strategy for Meth-induced neurodegenerative changes.

• Authors: Yuanhui Zhu, Xi Wang, Miaoyang Hu, Tingyu Yang, Huaisha Xu, Xiuwen Kang, Xufeng Chen, Lei Jiang, Rong Gao, Jun Wang
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2022 Pg. 3344569 ( 2022) ISSN: 1942-0994 [Electronic] United States
• PMID: 35633882 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Yuanhui Zhu et al.

Chemical References

• Amyloid beta-Peptides
• MAPT protein, human
• Qa-SNARE Proteins
• tau Proteins
• Methamphetamine

Topics

• Alzheimer Disease (chemically induced)
• Amyloid beta-Peptides (metabolism)
• Autophagy (physiology)
• Hippocampus (drug effects, metabolism, pathology)
• Humans
• Methamphetamine (toxicity)
• Neurons (drug effects, metabolism, pathology)
• Phosphorylation
• Qa-SNARE Proteins (metabolism)
• tau Proteins (metabolism)