Vaccination of Alzheimer's model mice with adenovirus vector containing quadrivalent foldable Abeta(1-15) reduces Abeta burden and behavioral impairment without Abeta-specific T cell response.
Active amyloid beta (Abeta) vaccination has been shown to be effective in clearing cerebral Abeta and improving cognitive function in mouse models of Alzheimer's disease (AD). The meningoencephalitis observed in AD vaccination trial was likely related to excessive T cell-mediated immunity caused by the immunogen Abeta(1-42). To avoid this toxicity, previous researchers have been using synthetic truncated Abeta derivatives that promote humoral immunity. In this study, we develop a novel adenovirus vaccine, which can express quadrivalent foldable Abeta(1-15) (4 x Abeta(15)) and gene adjuvant GM-CSF in vivo. Importantly, the 4 x Abeta(15) sequence includes an Abeta-specific B cell epitope but lacks the reported T cell epitope. The 4 x Abeta(15) adenovirus vaccine induces an Abeta-specific IgG1 predominant humoral immune response, and reduces brain Abeta deposition and cognition deficits in Tg2576 mice. Detection of IL-4 and IFN-gamma in restimulated splenocytes shows a significant Th2-polarized immune response. Stimulation of splenocytes with 4 x Abeta(15) peptides results in robust proliferative responses, whereas proliferation is absent after stimulation with full-length Abeta, which indicates that the 4 x Abeta(15) adenovirus vaccine does not induce Abeta-specific T cellular immune response. Thus, our results raise the possibility that adenovirus vector encoding 4 x Abeta(15) would be a promising candidate for future AD vaccination program.
Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, PR China.
Juntao
J
Zou
Zhibin
Z
Yao
Ge
G
Zhang
Huaqiao
H
Wang
Jie
J
Xu
David T
DT
Yew
E Lucy
EL
Forster
D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D016207:Cytokines / Q000134:cerebrospinal fluid; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005822:Genetic Vectors / Q000502:physiology; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D001523:Mental Disorders / Q000209:etiology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011930:Reaction Time; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination / Q000379:methods*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D010446:Peptide Fragments