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

Abstract

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 (AβpE3-X), which was found to be abundant in the patients' brain, has attracted much attention after the report that AβpE3-42 could serve as a template to exacerbate the aggregation of Aβ. In addition, AβpE3-X could not be recognized by the antibodies targeting the N-terminus of Aβ, suggesting that AβpE3-X maybe the ignored one. Indeed, passive immunization targeting AβpE3-X 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 AβpE3-X, which contains AβpE3-15 as B cell epitope and P2 as T cell epitope. We showed that this vaccine could induce strong antibody response to AβpE3-X. 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.