1Neuroscience Research Institute & Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
2Center for Translational Research of Neurology Disease, First Affi liated Hospital, Dalian Medical University, Dalian 116011, China
3Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga 849-8501, Japan
4Department of Neurology, Peking University Third Hospital, Beijing 100191, China
5Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
6Department of Neurology, Graduate School of Medicine, Juntendo University, Tokyo 113-0033, Japan
#These authors contributed equally to this work.
*Corresponding author: De-Hua Chui. E-mail: dchui@bjmu.edu.cn

Abstract 

The imbalance between β-amyloid (Aβ) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer’s disease (AD). The sporadic form of AD is characterized by an overall impairment in Aβ clearance. Immunotherapy targeting Aβ clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aβ clearance. We previously reported that oral vaccination with a recombinant AAV/Aβ vaccine increased the clearance of Aβ from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Aβ decreased the p62 level and up-regulated the LC3BII/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/mTOR pathway may account for autophagy enhancement. We also found increased anti-Aβ antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aβ clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention.

Keywords

oral vaccination; autophagy; Akt/mTOR pathway; Aβ clearance; Alzheimer’s disease

[SpringerLink]