A multi-targeting immunotherapy ameliorates multiple facets of Alzheimer’ s disease in 3xTg mice

Abstract Alzheimer’ s disease (AD) is a intricate disorder involving amyloid deposits, neurofibrillary tangles, and chronic neuroinflammation. Though current Aβ-directed immunotherapies effectively eliminate amyloid plaques, their limited clinical benefits and notable safety concerns arise from overlooking two other neglecting neurodegenerative features. Compelling evidence highlights synergistic cooperation between Aβ and tau, underscoring the imperative need of developing combinational therapies to target he diverse pathologies of Alzheimer's disease (AD). Our prior studies had demonstrated the effectiveness of Aβ epitope and hyperphosphorylated tau (pTau) epitope vaccines in reducing AD pathology in corresponding transgenic mouse models.. In this study, we present a dual AD vaccine combining Aβ and pTau vaccines, eliciting robust and enduring antibody responses against pathological Aβ and pTau in 3xTg transgenic mice. The combinational vaccine significantly eradicated Aβ plaques and pTau tangles, markedly enhancing cognitive abilities in AD model mice compared to individual vaccines. Additionally, the combined vaccine suppressed neuroinflammatory factors, including gliosis and proinflammatory cytokines. Mechanistically, peripheral antibodies from the dual vaccine penetrated the brain, recognizing and inhibiting Aβ and pTau aggregation, thereby reducing their cytotoxicity. In summary, this innovative multi-targeting immunotherapy remarkably ameliorates diverse AD pathologies, demonstrating maximum benefits in slowing the clinical progression of this heterogeneous disease.