A coimmunization vaccine of Aβ42 ameliorates cognitive deficits without brain inflammation in an Alzheimer’s disease model

Abstract

IntroductionVaccination against amyloid-β protein (Aβ42) induces high levels of antibody, making it a promising strategy for treating Alzheimer’s disease (AD). One drawback in the past was that clinical trial approval was withheld because of speculation that the Aβ42 vaccine induces CD4+ T cell infiltrations into the central nervous system. To reduce T-cell activation while concomitantly maintaining high anti-Aβ42 titers is a great challenge in immunology.MethodsWe aimed to demonstrate that coimmunization with Aβ42 protein and expression plasmid can be beneficial in a mouse AD model and can prevent inflammation. We immunized the AD mice with the coimmunization vaccine and assessed behavior change and Aβ42 deposition. Furthermore, to determine the safety of the coimmunization vaccine, we used an induced Aβ42-EAE model to mimic the meningoencephalitis that happened in the AN-1792 vaccine clinical phase II trial and tested whether the coimmunization vaccine could ameliorate T-cell-mediated brain inflammation.ResultsThe coimmunization vaccination reduced Aβ plaques and significantly ameliorated cognitive deficit while inhibiting T-cell-mediated brain inflammation and infiltration. These studies demonstrate that the coimmunization strategy that we describe in this article can ameliorate AD pathology without notable adverse effects in mice.ConclusionsA coimmunization strategy leading to the development of a safe immunotherapeutic/preventive protocol against AD in humans is warranted.

Vaccines targeting the primary amino acid sequence and conformational epitope of amyloid‐β had distinct effects on neuropathology and cognitive deficits in EAE/AD mice

“…Notably, our EAE/AD model exhibited considerable neuroinflammation following Aβ immunization, even without myelin basic protein induction. This suggests that Aβ, acting as a self‐protein, can induce autoimmune reactions in EAE/AD mice, which is consistent with previous reports (Marchese et al, 2014; Sardi et al, 2011; Wang et al, 2014). In contrast, AOE1 immunization did not promote neuroinflammation or detrimental immune responses.…”

Co-immunization with DNA and protein mixture: A safe and efficacious immunotherapeutic strategy for Alzheimer's disease in PDAPP mice

“…At the same time, co-immunization reduced the production of inflammatory cytokine IFN-γ and increased the production of IL-4 in CD4 + T cells, suggesting that an anti-inflammatory effect was induced in the co-immunized mice. Likewise, Wang et al recently reported that co-immunization with Aβ42 peptide and Aβ42-coding DNA ameliorated AD pathology while inhibiting Aβ42-specific T-cell-mediated inflammatory reactions in mice 43 , further supporting the feasibility of this approach. Moreover, the lack of adjuvant use with our combined vaccine is another advantage which can reduce potential side effects associated with strong adjuvants as reported in the AN-1792 and ACC-001 trials.…”

New progress in active immunotherapy targeting to amyloid beta

“…Another study by Wang and coworkers [32] demonstrated the efficiency of coimmunization with A42 and a plasmid expressing A42. They immunized APP 695 mice intramuscularly with a mixture of A42 and pVAX1-A42 which could express A42.…”