Affiliations: [a] Department of Pharmacology, Hangzhou Key Laboratory of Medical Neurobiology, School of Medicine, Hangzhou Normal University, Hangzhou, P.R. China | [b] Qiushi Academy of Advanced Studies, Zhejiang University, Hangzhou, P.R. China | [c] Department of Biomedical Engineering, Zhejiang Provincial Key Laboratory of Cardio-Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Zhejiang University, Hangzhou, P.R. China
Correspondence:
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Correspondence to: Dr. Yi Yang, Room 401, Building 8, Hangzhou Normal University, No. 16 Xuelin Street, Xiasha Higher Education Zone, Hangzhou 310036, Zhejiang, P.R. China. Tel.: +86 571 28865673; E-mail: [email protected]; Dr. Xiaoxiang Zheng, Room 505, Zhou Yiqing Building, Zhejiang University, No. 38 Zheda Road, Hangzhou 310027, Zhejiang, P.R. China. Tel./Fax: +86 571 87951091; E-mail: [email protected].
Abstract: Autophagy is a lysosomal degradative process essential for neuronal homeostasis, whereas autophagic failure has been linked to accumulating neurodegenerative disorders. However, the precise role of autophagy in axonal and dendritic degeneration in Alzheimer's disease (AD) remains unclear. In this study, we aim to investigate the precise effect of autophagy in amyloid-β peptide (Aβ)25-35-mediated neurite degeneration. Aβ35-25, the non-neurotoxic reverse sequence analogue of Aβ25-35, was used as a negative control. Our results showed that Aβ25-35 dose-dependently suppressed PC12 proliferation and induced autophagy induction in neurites (axons and dendrites). A high proportion of autophagic structures in PC12 neurites were autolysosomes after 24 h of Aβ25-35 treatment. Autophagy inhibition by 3-methyladenine (3MA), LY294002, and chloroquine (CQ) could not relieve the Aβ25-35-induced neurite degeneration, while administration of autophagy stimulator rapamycin or AR-12 efficiently suppressed neurite degeneration. Autophagosomes colocalized with fragmented mitochondria after Aβ25-35 treatment. Similar results were obtained using in vitro cultured superior cervical ganglion neurons. These findings demonstrate that autophagy stimulation may prevent neuritic degeneration following Aβ25-35 treatment. Upregulation of autophagic activity may provide a valuable approach for the treatment of axonal and dendritic dystrophy in AD patients.
