The development of therapeutic nanovaccine that elicits anti‐Aβ antibodies and Aβ‐specific regulatory T cells for the treatment of Alzheimer’s disease.

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a multi‐factorial cognitive disorder with complex pathogenesis including the accumulation of beta‐amyloid (Aβ) plaque and neuroinflammation. In previous studies, active immunotherapy injecting Aβ peptide as an antigen achieved the prophylaxis of Aβ accumulation by generating anti‐Aβ antibodies. Otherwise, the adoptive transfer of regulatory T (Treg) cells attenuated neuroinflammation by secreting anti‐inflammatory cytokines in the AD brain. To combine both approaches and improve the therapeutic efficacy against AD, we developed a nanovaccine that presents Aβ peptides as antigen and simultaneously induce the differentiation of naive T cells into Aβ‐specific Treg cells.MethodA lipid nanoparticle loaded with Aβ peptides and rapamycin (LNP‐R/Aβ) was intradermally injected once a week for five weeks into a transgenic AD mouse model, 5XFAD. The generation of Aβ‐specific antibodies in the plasma and brain was measured by indirect enzyme‐linked immunosorbent assay. Induction of Treg cells in the spleen was measured by flow cytometric analysis and RT‐qPCR analysis. The accumulation of Aβ aggregates in the brain and the level of neuroinflammation were evaluated by immunohistochemical and immunoblotting assay. The cognitive function of 5XFAD was assessed through the Morris water maze test.ResultAdministration of LNP‐R/Aβ generated anti‐Aβ polyclonal antibodies detecting the N‐terminus (Aβ1‐8) of the Aβ peptide. Also, the increased level of CD4+Foxp3+Treg cells was observed in the spleen and brain. The Treg cells induced by the LNP‐R/Aβ more efficiently reduced the Aβ plaque accumulation than general Treg cells, indicating that LNP‐R/Aβ promoted the generation of Aβ‐specific Treg cells. Also, the Aβ‐specific Treg cells led to the differentiation of microglia into anti‐inflammatory form of microglia secreting anti‐inflammatory cytokines such as TGF‐β1 and IL‐10. These changes resulted in a significantly decreased amount of Aβ plaques and the attenuated proliferation of reactive microglia and astrocyte in the 5XFAD mice brains. Furthermore, LNP‐R/Aβ injected 5XFAD mice showed improved learning and memory function in the Morris water maze test.ConclusionLNP‐R/Aβ proposes a novel approach to AD treatment that achieves synergistic therapeutic efficacy by combining the mode of action of anti‐Aβ antibodies and Aβ‐specific Treg cells.