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Alzheimer’s disease: Toward the rational design of an effective vaccine


The promising clinical results with the human monoclonal antibodies aducanumab and solanezumab targeting
β-amyloid in Alzheimer’s disease treatment, confirm both the amyloid cascade hypothesis and protective natural
immunity, while strengthening the immunotherapeutic approach. That aducanumab recognizes a conformational
epitope formed by oligomers emphasizes the need for whole β-amyloid, not just its B-cell epitopes as have been
the norm to avoid pro-inflammatory Th1-reactions.That truncated β-amyloid having N-terminal pyroglutamate is
present only in diseased brain implies a new useful vaccine antigen. Another relevant antigen is the tau protein,
which shows a close association and cooperativity with β-amyloid in exacerbating this disease. Hence, effective
vaccines may be polyvalent, presenting to the immune system a number of antigens relevant to induce an immune
response to prevent or slowdown the onset of this disease. The presence of both B and T cell epitopes in the antigens,
require a sole Th2 immunity to avert brain inflammation; a task that cannot be attain with adjuvants that under
any conditions induce Th1 and/or Th17 immunities. Hence, new vaccine adjuvants are need to safely induce Th2
while inhibiting Th1 immunity, an objective that can be achieved with certain fucosylated glycans or triterpene
glycosides, which apparently bind to the DC-SIGN lectin on dendritic cells polarizing the immune response toward
Th2 immunity. Because the triterpene glycosides have the pharmacophore needed to co-stimulate T cells, they may
ameliorate the T-cell anergy associated with immunosenescence and responsible for poor vaccine efficacy in the
elderly population, a critical issue for an Alzheimer’s vaccine.

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