Prophylactic Vaccine Based on Pyroglutamate‑3 Amyloid β Generates Strong Antibody Response and Rescues Cognitive Decline in Alzheimer’s Disease Model Mice

Clearance of amyloid β (Aβ) by immunotherapy is one of the fancy methods to treat Alzheimer’s disease (AD). However, the failure of some clinical trials suggested that there may be something ignored in the past development of immunotherapy. Pyroglutamate-3 Aβ (Aβ_{pE3‑<i>X</i>}), which was found to be abundant in the patients’ brain, has attracted much attention after the report that Aβ_pE3‑42 could serve as a template to exacerbate the aggregation of Aβ. In addition, Aβ_{pE3‑<i>X</i>} could not be recognized by the antibodies targeting the N-terminus of Aβ, suggesting that Aβ_{pE3‑<i>X</i>} maybe the ignored one. Indeed, passive immunization targeting Aβ_{pE3‑<i>X</i>} has shown some beneficial results, while active immunotherapy has not been extensively studied. In the present study, we designed and synthesized a novel peptide vaccine targeting Aβ_{pE3‑<i>X</i>}, which contains Aβ_pE3‑15 as B cell epitope and P2 as T cell epitope. We showed that this vaccine could induce strong antibody response to Aβ_{pE3‑<i>X</i>}. We also showed that prophylactic immunization of AD model mice with our vaccine could reduce Aβ plaques and rescue cognitive decline. This new kind of Aβ vaccine will open up new directions for AD immunotherapy