Cognitive-Performance Recovery of Alzheimer's Disease Model Mice by Modulation of Early Soluble Amyloidal Assemblies

摘要

Alzheimer's disease (AD), a neurodegenerative disorder for which there is no disease-modifying therapy, is the foremost cause of dementia in elderly people. An initial hypothesis suggested that fibrillar forms of β-amyloid polypeptide (Aβ) were responsible for neuronal dysfunction, but recent studies indicate soluble Aβ oligomers as the major toxic species. An attractive therapeutic strategy for AD is to block the oligomerization of soluble amyloid (Aβ) peptides. Herein we describe a novel oligomerization inhibitor whose mechanism of action is based on the targeting of aromatic recognition modules together with a unique C~α-methylation β-breakage strategy. This small molecule interacts with early intermediate assemblies of Aβ and inhibits their assembly into toxic oligomers. NMR spectroscopy indicates that the inhibitor interacts with the aromatic core of Aβ. The orally bioavailable compound is very safe and reduced the amount of amyloid deposits in the brain of AD model mice. Treatment with this novel compound led to the recovery of the cognitive performance of model mice to the level of nontransgenic mice.