Targeting isoD7 Neoepitope in Aβ for Alzheimer's Disease Immunotherapy.

Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) accumulation, neuroinflammation and cognitive impairment. During AD pathogenesis, Aβ undergoes several post-translational modifications, the most common of which is the isomerization of aspartic acid (isoD7-Aβ), a modification that contributes to the disease development. Passive immunization with isoD7-Aβ-specific antibodies reduced cognitive impairment and amyloid deposition in 5xFAD mice. However, therapeutic application of anti-Aβ antibodies has important limitations, emphasizing the need for alternative approaches. Here, we evaluated the efficacy of isoD7-Aβ1-16-targeting immunization compared with Aβ1-16-targeting immunization on AD pathogenesis in APP/PS1 mice. Both isoD7-Aβ1-16 and Aβ1-16, conjugated with ovalbumin, induced Aβ1-16 - specific memory B cells and IgG in mice. However, only isoD7-Aβ1-16 conjugate promoted B cell and IgG response to the neoepitopes on isoD7-Aβ1-16. In the Y-maze test, only APP/PS1 mice immunized with isoD7-Aβ1-16 at 3 months of age retained spatial memory as they aged, in contrast to APP/PS1 mice immunized with Aβ1-16 at the same age. Immunization with both isoD7-Aβ1-16 and Aβ1-16 significantly reduced amyloid burden, lowered microglial and astrocyte activation. Furthermore, we assessed the effect of immunization in APP/PS1 mice at a later stage of AD pathogenesis, at 6 months of age. Even at the stage of advanced disease, immunization with isoD7-Aβ1-16 strongly impeded the formation of amyloid plaques and reduced brain-wide microglial and astrocyte activation, in contrast to immunization with Aβ1-16. Our results indicate the promise of targeting isoD7-Aβ for active AD immunotherapy, both for preventing the development of the pathology at its early stage and for ceasing the advanced AD pathogenesis.