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

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.

The Additive Effects of Low Dose Intake of Ferulic Acid, Phosphatidylserine and Curcumin, Not Alone, Improve Cognitive Function in APPswe/PS1dE9 Transgenic Mice

“…73) Myricetin inhibits Aβ production via α-secretase activation and β-secretase inhibition, 74) inhibits Aβ aggregation, 8,75) and promotes an increase in BDNF. 76) Taxifolin inhibits Aβ production via β-secretase up-regulation, 77) inhibits Aβ aggregation, 78,79) and inhibits AChE activity. 80) Although a clinical trial on a quercetin-rich onion powder was conducted, 81) it was difficult to judge the effectiveness of the powder because the scale of the trial was very small (N = 4 to 5 people).…”

Potential Therapeutic Approaches for Cerebral Amyloid Angiopathy and Alzheimer’s Disease

“…Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease that results from amyloid-β (Aβ) deposition in the cerebrovasculature [1][2][3][4][5]. CAA is associated with cerebrovascular alterations and an increased risk of intracerebral hemorrhage, which can cause cognitive impairment [1][2][3][4][5][6].…”

“…Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease that results from amyloid-β (Aβ) deposition in the cerebrovasculature [1][2][3][4][5]. CAA is associated with cerebrovascular alterations and an increased risk of intracerebral hemorrhage, which can cause cognitive impairment [1][2][3][4][5][6]. The frequency and severity of CAA increase with aging, and CAA is often accompanied by Alzheimer's disease (AD) and vascular cognitive impairment [1][2][3][4][5][6].…”

“…CAA is associated with cerebrovascular alterations and an increased risk of intracerebral hemorrhage, which can cause cognitive impairment [1][2][3][4][5][6]. The frequency and severity of CAA increase with aging, and CAA is often accompanied by Alzheimer's disease (AD) and vascular cognitive impairment [1][2][3][4][5][6]. However, predictive markers and effective treatments for CAA have not been established.…”

“…These studies have elucidated the issues that need to be addressed for effective CAA and AD treatment. We recently provided the first evidence that in a mouse model of CAA, oral administration of taxifolin, a natural bioactive flavonoid, prevented cognitive impairment through pleiotropic beneficial effects [3,4]. Furthermore, a potential novel predictive blood marker for the development of dementia was recently identified based on a population-based longitudinal study [17].…”