Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models

Background: Aggregated amyloid-beta (A beta) is considered a pathogenic initiator of Alzheimer's disease (AD), in strong association with tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and cognitive decline. As the removal of amyloid burden from AD patient brains by antibodies has shown therapeutic potential, the development of small molecule drugs inducing chemical dissociation and clearance of AP is compelling as a therapeutic strategy. In this study, we synthesized and screened aryloxypropanolamine derivatives and identified 1-(3-(2,4-di-tert-pentylphenoxy)-2-hydroxypropyl)pyrrolidin-1-ium chloride, YIAD002, as a strong dissociator of A beta aggregates. Methods: The dissociative activity of aryloxypropanolamine derivatives against A beta aggregates were evaluated through in vitro assays. Immunohistochemical staining, immunoblot assays, and the Morris water maze were used to assess the anti-Alzheimer potential in YIAD002-treated 5XFAD and transgenic APP/PS1 mice. Target-ligand interaction mechanism was characterized via a combination of peptide mapping, fluorescence dissociation assays, and constrained docking simulations. Results: Among 11 aryloxypropanolamine derivatives, YIAD002 exerted strongest dissociative activity against beta-sheet-rich AP aggregates. Upon oral administration, YIAD002 substantially reduced amyloid burden and accordingly, improved cognitive performance in the Morris water maze and attenuated major pathological hallmarks of AD including tauopathy, neuroinflammation, and synaptic protein loss. Mechanism studies suggest that YIAD002 interferes with intermolecular beta-sheet fibrillation by directly interacting with KLVFFA and IGLMVG domains of AP. In addition,YIAD002 was found to possess dissociative activity against aggregates of pyroglutamate-modified AP and tau. Conclusions: Collectively, our results evince the potential of chemical-driven dissociation of AP aggregates by aryloxypropanolamines as a therapeutic modality of the amyloid clearance approach.

Automated summary

The study identified YIAD002 as a potent dissociator of Aβ aggregates, showing significant reduction in amyloid burden, improved cognitive performance, and alleviated major pathological hallmarks of AD. Mechanism studies suggest that YIAD002 interferes with intermolecular beta-sheet fibrillation by directly interacting with specific domains of Aβ.