title: Autophagy is involved in oral rAAV/Aβ vaccine-induced Aβ clearance in APP/PS1 transgenic mice.
abstract: The imbalance between ß-amyloid (Aß) 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 Aß clearance. Immunotherapy targeting Aß 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 Aß clearance. We previously reported that oral vaccination with a recombinant AAV/Aß vaccine increased the clearance of Aß 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/Aß decreased the p62 level and up-regulated the LC3B-II/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-Aß 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 Aß clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention.
authors.affiliation: Neuroscience Research Institute & Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: He-Cheng
authors.initials: HC
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Bolati
authors.initials: B
authors.lastname: Kuerban
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Jin
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
authors.forename: Hideo
authors.initials: H
authors.lastname: Hara
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Fan
authors.forename: Yan-Jiang
authors.initials: YJ
authors.lastname: Wang
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tabira
authors.forename: De-Hua
authors.initials: DH
authors.lastname: Chui
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000378:metabolism* / Q000517:prevention & control; D023582:Alzheimer Vaccines / Q000008:administration & dosage*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D000229:Dependovirus; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000008:administration & dosage*; D053764:Presenilin-1 / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D011994:Recombinant Proteins; C098994:amyloid beta-protein (1-43); C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases