title: 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-β1-40accumulation 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-β1-40assembly. 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.
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan. saitosa@ncvc.go.jp.|Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan. saitosa@ncvc.go.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.affiliation: Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan.
authors.forename: Yorito
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Department of CNS Research, Otsuka Pharmaceutical Co., Ltd, Tokushima, 771-0192, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd, Tokushima, 771-0192, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan.|Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center, Suita, 565-8565, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Harada-Shiba
authors.affiliation: Institute for Ageing and Health, NIHR Biomedical Research Building, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.affiliation: Department of MediScience, Translational Research Informatics Center, Foundation for Biomedical Research and Innovation, Kobe, 650-0047, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukushima
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan. ihara@ncvc.go.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016657:Cerebral Amyloid Angiopathy / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D011794:Quercetin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011897:Random Allocation; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D065852:Spatial Memory / Q000187:drug effects* / Q000502:physiology
chemical_list: C000593873:Ager protein, mouse; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D000067759:Receptor for Advanced Glycation End Products; D011794:Quercetin; C003377:taxifolin
keywords: Alzheimer’s disease; Cerebral amyloid angiopathy; Oligomer; Taxifolin; Treatment