Work

IK‐5f targets amyloid aggregates and alleviates cognitive deficits in the 5XFAD Alzheimer mouse model

Year: 2025

Type: article

Abstract: BACKGROUND: Alzheimer's disease (AD) involves progressive synaptic dysfunction and extracellular deposition of amyloid-β (Aβ) plaques. Current immunotherapies targeting Aβ are effective but associated with amyloid-related imaging abnormalities. Small-molecule drugs that disaggregate Aβ aggregates may provide a safer, cost-effective alternative. METHOD: Six novel chemical compounds were synthesized and screened for anti-Aβ activity using Thioflavin T fluorescence assays. IK-5f, the most effective compound, was evaluated in 5XFAD mice via a four-week intraperitoneal injection regimen. Cognitive performance was assessed using the Y-maze test, and Aβ plaques and neuroinflammation were analyzed through immunohistochemical staining and dot blot assays. RESULT: IK-5f significantly inhibited Aβ aggregation and promoted fibril dissociation in vitro. In 5XFAD mice, IK-5f improved cognitive performance in the Y-maze test, reduced hippocampal Aβ plaque burden, and decreased neuroinflammation, as evidenced by reduced GFAP staining and 6E10-immunoreactive aggregates. CONCLUSION: IK-5f exhibits strong potential as a small-molecule drug candidate for AD by effectively reducing Aβ pathology and neuroinflammation while enhancing cognitive function.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz70859_101506