An Immunomodulatory Therapeutic Vaccine Targeting Oligomeric Amyloid-β

Article type: Research Article

Authors: Song, Ge^a | Yang, Haiqiang^b | Shen, Ning^b | Pham, Phillip^c | Brown, Breanna^c | Lin, Xiaoyang^c | Hong, Yuzhu^c | Sinu, Paul^c | Cai, Jianfeng^b | Li, Xiaopeng^b | Leon, Michael^c | Gordon, Marcia N.^d | Morgan, David^d | Zhang, Sai^e | Cao, Chuanhai^{b; c; f; *}

Affiliations: [a] Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China | [b] College of Arts and Science, University of South Florida, Tampa, FL, USA | [c] Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA | [d] Department of Translational Neuroscience, College of Medicine, Michigan State University, Grand Rapids, MI, USA | [e] Institution of Brain Trauma and Neurology Disease, Key Laboratory of Neurotrauma Repair of Tianjin, Tianjin, China | [f] College of Medicine, University of South Florida, Tampa, FL, USA

Correspondence: [*] Correspondence to: Chuanhai Cao, PhD, Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA. Tel.: +1 813 396 0742; E-mail: [email protected].

Abstract: Background:Aging is considered the most important risk factor for Alzheimer’s disease (AD). Recent research supports the theory that immunotherapy targeting the “oligomeric” forms of amyloid-β (Aβ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ, called AN1792, was suspended due to cases of meningoencephalitis in patients. Objective:To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer Aβ and prevent an autoimmune response. Methods:Double transgenic APPswe/PS1ΔE9 (Tg) and C57BL/6J control mice were used in this study. Cytokine expression profile detection, characterization of antisera, brain GSK-3β, LC3 expression, and spatial working memory testing before and post-vaccination were obtained. Results:Epitope prediction indicated that E22W42 could generate 13 new T cell epitopes which can strengthen immunity in aged subjects and silence several T cell epitopes of the wild type Aβ. The silenced T cell epitope could help avoid the autoimmune response that was seen in some patients of the AN-1792 vaccine. The E22W42 not only helped sensitize bone marrow-derived DCs for the development of an oligomeric Aβ-specific antibody, but also delayed memory impairment in the APP/PS1 mouse model. Most importantly, this E22W42 peptide will not alter the DC’s natural immunomodulatory properties. Conclusion:The E22W42 vaccine is possibly safer for patients with impaired immune systems. Since there is increasing evidence that oligomeric form of Aβ are the toxic species to neurons, the E22W42 antibody’s specificity for these “oligomeric” Aβ species could provide the opportunity to produce some clinical benefits in AD subjects.

Keywords: Alzheimer’s disease, antibody, dendritic cells, T cell epitope, vaccine

DOI: 10.3233/JAD-200413

Journal: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1639-1653, 2020