Development of a Novel Alzheimer's Disease Model Based on the Theory of the Toxic-conformer of Amyloid β

Abstract

Development of therapeutics for Alzheimer's disease (AD) is an urgent research task. Amyloid β (Aβ) is one of the causative proteins of AD. Irie et al. identified a toxic conformer among the various structures of 42-mer Aβ (Aβ42). This conformer, which possesses a turn structure at the positions Glu22-Asp23, exhibits rapid oligomerization and potent neurotoxicity. By the generation of conformationally-specific antibodies against this toxic conformer of Aβ, elevation of the toxic conformer in the AD brain was strongly suggested. To investigate the pathogenic role of the toxic conformer in AD, passive immunization experiments against conventional AD model mice were conducted. Specific antibody administration improved the behavioral abnormalities observed in AD model mice without affecting senile plaque pathology. Next, knock-in mice exclusively producing the toxic conformer of Aβ were generated. These mice exhibited cognitive dysfunction and oligomerization of Aβ, which preceded the onset of the plaque deposition. Taken together, the toxic conformer of Aβ is confirmed to be involved in the pathogenesis of AD, and our knock-in mice could be useful in analyzing the Aβ oligomer-related pathology of AD.