Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) induces various forms of cerebral infarcts and hemorrhages from vascular amyloid-beta accumulation, resulting in acceleration of cognitive impairment, which is currently untreatable. Soluble amyloid-beta protein likely impairs cerebrovascular integrity as well as cognitive function in early stage Alzheimer's disease. Taxifolin, a flavonol with strong anti-oxidative and anti-glycation activities, has been reported to disassemble amyloid-beta in vitro but the in vivo relevance remains unknown. Here, we investigated whether taxifolin has therapeutic potential in attenuating CAA, hypothesizing that inhibiting amyloid-beta assembly may facilitate its clearance through several elimination pathways. Vehicle- or taxifolin-treated Tg-SwDI mice (commonly used to model CAA) were used in this investigation. Cognitive and cerebrovascular function, as well as the solubility and oligomerization of brain amyloid-beta proteins, were investigated. Spatial reference memory was assessed by water maze test. Cerebral blood flow was measured with laser speckle flowmetry and cerebrovascular reactivity evaluated by monitoring cerebral blood flow changes in response to hypercapnia. Significantly reduced cerebrovascular pan-amyloid-beta and amyloid-beta(1-40) accumulation was found in taxifolin-treated Tg-SwDI mice compared to vehicle-treated counterparts (n = 5). Spatial reference memory was severely impaired in vehicle-treated Tg-SwDI mice but normalized after taxifolin treatment, with scoring similar to wild type mice (n = 10-17). Furthermore, taxifolin completely restored decreased cerebral blood flow and cerebrovascular reactivity in Tg-SwDI mice (n = 4-6). An in vitro thioflavin-T assay showed taxifolin treatment resulted in efficient inhibition of amyloid-beta(1-40) assembly. In addition, a filter trap assay and ELISA showed Tg-SwDI mouse brain homogenates exhibited significantly reduced levels of amyloid-beta oligomers in vivo after taxifolin treatment (n = 4-5), suggesting the effects of taxifolin on CAA are attributable to the inhibition of amyloid-beta oligomer formation. In conclusion, taxifolin prevents amyloid-beta oligomer assembly and fully sustains cognitive and cerebrovascular function in a CAA model mice. Taxifolin thus appears a promising therapeutic approach for CAA.