Developing Topics.

Background: Peptide antigens that mimic disease-related conformations of Aβ and tau were designed and created, and antibodies against these peptide antigens were generated and characterized.

Method: The peptide antigens were designed to mimic β-strands formed by Aβ and tau in the cryo-EM structures of the Alzheimer's disease brain-derived fibrils. Peptide antigens were also designed to mimic β-hairpins of Aβ and oligomers formed by the β-hairpins. These β-strand and β-hairpin antigens were then used to generate antibodies in rodents. Ex vivo immunohistochemical and biochemical studies in Alzheimer's disease brain-tissue and cell-based studies were performed to characterize the antibodies.

Result: The antibodies raised against the Aβ-derived peptide antigens recognized Aβ plaques in Alzheimer's disease brain tissue and in 5xFAD mouse brains and protected iPSC-derived human neurons from Aβ toxicity. Biochemical characterization of these Aβ-derived antibodies showed that the antibodies exhibit some selectivity for aggregated forms of Aβ. The antibodies raised against the tau-derived peptide antigens recognized tau neurofibrillary tangles in Alzheimer's disease brain tissue and inhibited tau seeding in a cell-based tau biosensor assay.

Conclusion: Antibodies generated against conformationally constrained β-strand and β-hairpin antigens designed to mimic disease-related conformations of Aβ and tau exhibit characteristics beneficial for immunotherapy, such as recognition of Aβ and tau pathology, and protection against Aβ cytotoxicity and inhibition of tau seeding.