A Therapeutic Nanovaccine that Generates Anti-Amyloid Antibodies and Amyloid-specific Regulatory T Cells for Alzheimer's Disease

Abstract

Alzheimer's disease (AD), the most common cause of dementia, is a complex condition characterized by multiple pathophysiological mechanisms including amyloid-beta (A beta) plaque accumulation and neuroinflammation in the brain. The current immunotherapy approaches, such as anti-A beta monoclonal antibody (mAb) therapy, A beta vaccines, and adoptive regulatory T (Treg) cell transfer, target a single pathophysiological mechanism, which may lead to unsatisfactory therapeutic efficacy. Furthermore, A beta vaccines often induce T helper 1 (Th1) cell-mediated inflammatory responses. Here, a nanovaccine composed of lipid nanoparticles loaded with A beta peptides and rapamycin is developed, which targets multiple pathophysiological mechanisms, exhibits the combined effects of anti-A beta antibody therapy and adoptive A beta-specific Treg cell transfer, and can overcome the limitations of current immunotherapy approaches for AD. The Nanovaccine effectively delivers rapamycin and A beta peptides to dendritic cells, produces both anti-A beta antibodies and A beta-specific Treg cells, removes A beta plaques in the brain, alleviates neuroinflammation, prevents Th1 cell-mediated excessive immune responses, and inhibits cognitive impairment in mice. The nanovaccine shows higher efficacy in cognitive recovery than an A beta vaccine. Unlike anti-A beta mAb therapy and adoptive Treg cell transfer, both of which require complicated and costly manufacturing processes, the nanovaccine is easy-to-prepare and cost-effective. The nanovaccines can represent a novel treatment option for AD.