Mosaic Display of Multivalent Tau and A-Beta peptides on Immunogenic SNAP Liposomes

Project Summary/Abstract Alzheimer’s disease (AD) currently affects ~6.2 million Americans, and this number is projected to increase to 14 million by 2060 unless novel treatments or interventions to prevent or delay the onset of AD are identified. Harnessing the immune system to prevent or remove Aβ and/or tau pathologies represents a promising disease- modifying therapeutic approach for the treatment of AD. Currently, all the previous and ongoing immunotherapy studies target only one epitope of either Aβ or tau protein. Because most AD cases are multifactorial, and sporadic AD is caused by multiple mechanisms, it is unlikely that a single target will be sufficient to stop or reduce the progression of AD. Based on the role of Aβ and tau in the pathogenesis of AD, immunotherapy simultaneously targeting multiple epitopes of both Aβ and tau may present a promising approach for AD drug development. The long-term objective of the proposed project is to develop a novel, effective vaccine for AD. The specific goal of this project is to develop a multivalent "mosaic" vaccine, termed SNAP-AD, targeting multiple epitopes of Aβ and tau simultaneously with the spontaneous nanoliposome antigen particle (SNAP) platform and to investigate its therapeutic effects for treating AD in a transgenic mouse model. Our working hypothesis is that immunotherapy simultaneously targeting the multiple epitopes of both Aβ and tau is a promising approach for developing effective AD therapeutics. To test this novel hypothesis, we propose three specific aims: (1) Formulate and characterize SNAP-AD, a mosaic nanoparticle vaccine comprising three tau and two Aβ peptide epitopes. POP BIO will formulate and characterize the pentavalent SNAP-AD vaccine simultaneously targeting tau at one N-terminal region (Tau 6-18), one mid-region (Tau 184-195), and one C-terminal region (pS396/S404), as well as N-terminal Aβ (1-14) and N-terminal pyroglutamate Aβ (pE3-14), and develop a manufacturing method with reproducible batch-to-batch characterization and the protocols to quantify each peptide and immunogenic lipid component. (2) Assess SNAP-AD for immune interference, Th1-biased cellular response, neuroinflammation, and antibodies’ durability. Immune interference will be assessed amongst the 5-plex immunogens, and if observed, possible ramification methods will be tested. Cellular responses, Th1/Th2 bias of the antibody response, and the antibodies’ durability induced by SNAP-AD will be probed. (3) Determine SNAP- AD efficacy using the 3xTg-AD mouse model. Ten-month-old 3xTg-AD mice and age-matched wild-type mice will be immunized with SNAP-AD and boosted twice with a four-week interval. One month after the third dose of immunization, behavioral tests, including general behavior, anxiety, locomotor activity, and cognitive function, will be conducted, and Aβ and tau pathology will be investigated both biochemically/immunohistochemically. The proposed studies will reveal whether the multivalent immunotherapy approach has promising therapeutic effects on AD pathologies and cognitive impairment. A positive outcome of this project would potentially lead to a novel vaccine for the treatment of AD, which will improve the quality of life of individuals with AD.