Cited by 110Alzheimer's disease research and treatmentsIntracerebral and Subarachnoid Hemorrhage ResearchNeurological Disease Mechanisms and Treatments

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

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Saito, Satoshi, Yamamoto, Yumi, Maki, Takakuni, Hattori, Yorito, Ito, Hideki, Mizuno, Katsuhiko, Harada-Shiba, Mariko, Kalaria, Raj N. +3 more·2017·Acta Neuropathologica Communications

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-β 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-β 1-40 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.

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  • Deposition of amyloid-β within microvessels is highly frequent in patients with Alzheimer's disease dementia and is associated with reduced blood flow in transgenic mouse models and humans.

    “Deposition of amyloid-β within microvessels is highly frequent in patients with Alzheimer’s disease dementia (Kalaria, 2016) and associated with reduced blood flow in transgenic mouse models (Han et al., 2008; Saito et al., 2017) and humans (Chung et al., 2009; Dumas et al., 2012).”

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Authors
Saito, S., Yamamoto, Y., Maki, T., Hattori, Y., Ito, H., Mizuno, K., Harada-Shiba, M., Kalaria, R. N., Fukushima, M., Takahashi, R., & Ihara, M.
Affiliations
  • National Cerebral and Cardiovascular Center (JP)
  • Kyoto University (JP)
  • Otsuka (Japan) (JP)
  • Newcastle University (GB)
  • Translational Research Informatics Center (Japan) (JP)
Corresponding author
Ihara, Masafumi
Venue
Acta Neuropathologica Communications
Published
2017-04-04
Volume
5
Issue
1
Pages
26-26
ISSN
2051-5960 (ISSN-L)
OpenAlex
W2599534399
Cited by
110
References
78
Citations by year
2026: 9 · 2025: 20 · 2024: 8 · 2023: 17 · 2022: 12 · 2021: 17 · 2020: 11 · 2019: 10 · 2018: 5 · 2017: 1
FWCI
5.47
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
Funders
  • Otsuka Pharmaceutical Company
  • Ministry of Education, Culture, Sports, Science and Technology (15H04271)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
taxifolin, cerebral amyloid angiopathy, amyloid-beta oligomerization, Aβ40, flavonols, cognitive impairment, spatial reference memory, cerebrovascular integrity, cerebral blood flow, cerebrovascular reactivity, Alzheimer's disease, anti-glycation agents
MeSH terms
Receptor for Advanced Glycation End Products, Animals, Cerebrovascular Circulation, Disease Models, Animal, Humans, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Quercetin, Random Allocation, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Neuroprotective Agents, Nootropic Agents, Spatial Memory, Protein Aggregation, Pathological

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