A Toxic Conformer of Aβ42 with a Turn at 22-23 is a Novel Therapeutic Target for Alzheimer's Disease

Immunotherapy targeting Aβ42 is drawing attention as a possible therapeutic approach for Alzheimer's disease (AD). Considering the significance of reported oligomerized Aβ42 species, selective targeting of the oligomer will increase the therapeutic efficacy. However, what kinds of oligomers are suitable targets for immunotherapy remains unclear. We previously identified a toxic conformer of Aβ42, which has a turn structure at 22-23 ("toxic turn"), among Aβ42 conformations. This toxic conformer of Aβ42 has been reported to show rapid oligomerization and to exhibit strong neurotoxicity and synaptotoxicity. We recently developed a monoclonal antibody against the toxic conformer (24B3), which demonstrated the increase of the toxic conformer in the cerebrospinal fluid of AD patients, indicating its accumulation in AD patients' brains. In this study, we evaluated the therapeutic efficacy of 24B3 targeting the toxic conformer in AD model mice. The intraperitoneal administration of 24B3 for 3 months improved cognitive impairment and reduced the toxic conformer levels. Notably, this treatment did not reduce the number of senile plaques. Furthermore, the single intravenous administration of 24B3 suppressed the memory deficit in AD mice. These results suggest that the toxic conformer of Aβ42 with a turn at 22-23 represents one of the promising therapeutic targets.