4-Acyl-3,4-dihydropyrrolo[1,2-a]pyrazine Derivative Rescued the Hippocampal-Dependent Cognitive Decline of 5XFAD Transgenic Mice by Dissociating Soluble and Insoluble Aβ Aggregates

Cerebral amyloid-beta (A beta) deposition is a representative hallmark of Alzheimer's disease (AD). Development of A beta-clearing small molecules could be an advantageous therapeutic strategy for A beta clearance considering the advantages in terms of side effects, cost-effectiveness, stability, and oral bioavailability. Here, we report an A beta-dissociating small molecule, YIAD-0121, a derivative of 4-acyl-3,4-dihydropyrrolo[1,2-alpha]pyrazine. Through a series of anti-A beta screening assays, YIAD-0121 was identified to inhibit A beta aggregation and dissociate preformed A beta fibrils in vitro. Furthermore, the administration of YIAD-0121 in 5XFAD transgenic AD mice inhibited the increase of cerebral A beta aggregation and progression of hippocampus-dependent cognitive decline, with ameliorated neuroinflammation.

Automated summary

YIAD-0121 is a small molecule that can dissociate preformed amyloid-beta fibrils. In vitro experiments showed that YIAD-0121 can inhibit the aggregation of amyloid-beta. Treatment with YIAD-0121 in transgenic AD mice prevented the increase of cerebral amyloid-beta aggregation and slowed down the progression of hippocampus-dependent cognitive decline, along with reduced neuroinflammation.