Abstract
Cerebral amyloid angiopathy (CAA) induces various forms of cerebral infarcts and hemorrhages from vascular amyloid-β accumulation, resulting in acceleration of cognitive impairment, which is currently untreatable. Soluble amyloid-β 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-β in vitro but the in vivo relevance remains unknown. Here, we investigated whether taxifolin has therapeutic potential in attenuating CAA, hypothesizing that inhibiting amyloid-β 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-β 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-β and amyloid-β1-40 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-β1-40 assembly. In addition, a filter trap assay and ELISA showed Tg-SwDI mouse brain homogenates exhibited significantly reduced levels of amyloid-β oligomers in vivo after taxifolin treatment (n = 4–5), suggesting the effects of taxifolin on CAA are attributable to the inhibition of amyloid-β oligomer formation. In conclusion, taxifolin prevents amyloid-β oligomer assembly and fully sustains cognitive and cerebrovascular function in a CAA model mice. Taxifolin thus appears a promising therapeutic approach for CAA.
Highlights
Cerebral amyloid angiopathy (CAA) is pathologically characterized by the deposition of amyloid-β within small cerebral vessels
Pharmacokinetics and safety profile of taxifolin We firstly investigated the pharmacokinetic profile of taxifolin in 8-week-old wild type (WT) mice given by solution orally via gavage
In 300 mg/kg taxifolin-treated mice, maximum concentration (Cmax) and elimination half-life period were recorded as 18.87 μM (5741 ng/mL) and 0.67 h, respectively, as in previous rat studies [70]
Summary
Cerebral amyloid angiopathy (CAA) is pathologically characterized by the deposition of amyloid-β within small cerebral vessels. Amyloid-β deposition within cerebral capillaries has been consistently associated with the apolipoprotein E ε4 allele and is frequently concomitant with Alzheimer’s disease [66]. CAA has been associated with Alzheimer’s disease in community-based older persons [8]. Recent pathological reports have shown that CAA is extremely common in sporadic Alzheimer’s disease [35], suggesting a strong, bidirectional relationship. Some forms of familial Alzheimer’s disease and Down syndrome frequently exhibit CAA [56, 74]. CAA is commonly regarded as a pathological hallmark of Alzheimer’s disease, in parallel to senile plaque and neurofibrillary tangle deposition [17, 25]
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