Therapeutic nanoliposome vaccine targeting multiple Aβ and tau epitopes reduces AD-like brain pathologies and rescues cognitive deficits in 3xTg-AD mice

Amyloid beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles (NFTs) are the histopathological hallmarks of Alzheimer's disease (AD) and targets for AD therapeutics. Since Aβ and tau pathologies both drive AD pathogenesis and progression, immunotherapies singularly targeting either Aβ or tau may be limited, and simultaneously targeting multiple epitopes of both Aβ and tau may be an efficacious approach. We developed a novel vaccine including three his-tagged tau peptides, tau_1-22, mid-region tau_171-191 (tau_pT181), and tau_388-407 (tau_pS396/S404), as well as two his-tagged Aβ fragments (N-terminal Aβ_1-14 and N-terminal pyroglutamate Aβ_pE3-14) with the spontaneous nanoliposome antigen particle (SNAP) system, termed SNAP-AD₅. Intramuscular vaccination of nine to ten months old of 3xTg-AD mice and age-matched wild-type control animals with SNAP-AD₅ or adjuvant only, once every three weeks for a total of 5 immunizations, simultaneously produced IgG titers of antibody against their specific antigens, significantly decreased Aβ and tau pathologies, and effectively improved cognitive function. SNAP-AD₅ was well tolerated without any detectable adverse side effects, including inflammatory responses in the peripheral circulation and in the brain, and hemorrhages in the mouse brain. These results support that SNAP-AD₅ simultaneously targeting both Aβ and tau is potentially a promising new approach for treating AD. Further optimization and development of the SNAP-AD₅ vaccine for treating AD is warranted.