A small molecule modulating heterogeneous amyloid-β isoforms improves cognitive and pathological outcomes in acute and 5XFAD Alzheimer's disease models.

Abstract

Background: Alzheimer's disease (AD) is characterized by the pathological aggregation of amyloid-β (Aβ) peptides into neurotoxic assemblies. While recent antibody therapies targeting Aβ have shown clinical efficacy, they face limitations including specificity for particular Aβ species and accessibility challenges. The structural heterogeneity of Aβ isoforms, including Aβ₄₀, Aβ₄₂, and pyroglutamate-modified Aβ_pE3-42, necessitates therapeutic strategies with broad-spectrum activity.

Methods: The effects of YIAD-1003, a dihydropyrrolo[1,2-a]pyrazine derivative, were evaluated in vitro using Thioflavin T fluorescence assays and A11 dot blot to assess fibrillization and dissociation of preformed aggregates across Aβ₄₀, Aβ₄₂, and Aβ_pE3-42. In vivo efficacy was examined in an acute Aβ₄₂-induced AD model and in 5XFAD transgenic mice. Cognitive performance was assessed using spatial and associative memory tests. Amyloid pathology, including soluble Aβ and fibrillar deposition, and neuroinflammation markers were quantified by biochemical and histological analyses.

Results: YIAD-1003 inhibited fibril formation and promoted dissociation of preformed aggregates across multiple Aβ isoforms in vitro. In the acute model, co-administration of YIAD-1003 ameliorated Aβ₄₂-induced memory impairment. In 5XFAD mice, oral administration improved cognitive performance, reduced plaque burden and soluble Aβ levels, and attenuated pathological alterations associated with neuroinflammation.

Conclusions: YIAD-1003, a dihydropyrrolo[1,2-a]pyrazine derivative, exhibits broad-spectrum intervention in Aβ assembly across multiple isoforms and confers functional and pathological benefits in AD mouse models. These findings support the development of multi-isoform small-molecule modulators as a possible AD therapeutic strategy.