| First Author | Lee HY | Year | 2022 |
| Journal | Alzheimers Res Ther | Volume | 14 |
| Issue | 1 | Pages | 177 |
| PubMed ID | 36443837 | Mgi Jnum | J:351743 |
| Mgi Id | MGI:7663164 | Doi | 10.1186/s13195-022-01112-6 |
| Citation | Lee HY, et al. (2022) Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models. Alzheimers Res Ther 14(1):177 |
| abstractText | BACKGROUND: Aggregated amyloid-beta (Abeta) 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 Abeta 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 Abeta aggregates. METHODS: The dissociative activity of aryloxypropanolamine derivatives against Abeta 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 Abeta 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 Abeta. In addition, YIAD002 was found to possess dissociative activity against aggregates of pyroglutamate-modified Abeta and tau. CONCLUSIONS: Collectively, our results evince the potential of chemical-driven dissociation of Abeta aggregates by aryloxypropanolamines as a therapeutic modality of the amyloid clearance approach. |
