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陕西快乐十分任五胆拖:Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy
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Cerebrovascular amyloid-β deposition is highly implicated in the pathogenesis of cerebral amyloid angiopathy (CAA), one of the major causes of dementia. We previously showed that orally administered taxifolin, a natural bioactive flavonoid, enhanced the clearance of amyloid-β, improved cerebral blood flow, and suppressed cognitive decline in a mouse model of CAA. Here we investigate the in vivo effects of taxifolin on intracerebral factors associated with neuronal injury in these mice. We find that orally administered taxifolin may have neuroprotective effects through suppressing intracerebral amyloid-β production, neuroinflammation, and oxidative tissue damage, despite the low permeability of the blood–brain barrier to taxifolin. Our findings suggest taxifolin as a potential target for clinical applications to prevent/treat CAA.
Cerebral amyloid angiopathy (CAA) results from amyloid-β deposition in the cerebrovasculature. It is frequently accompanied by Alzheimer’s disease and causes dementia. We recently demonstrated that in a mouse model of CAA, taxifolin improved cerebral blood flow, promoted amyloid-β removal from the brain, and prevented cognitive dysfunction when administered orally. Here we showed that taxifolin inhibited the intracerebral production of amyloid-β through suppressing the ApoE–ERK1/2–amyloid-β precursor protein axis, despite the low permeability of the blood–brain barrier to taxifolin. Higher expression levels of triggering receptor expressed on myeloid cell 2 (TREM2) were associated with the exacerbation of inflammation in the brain. Taxifolin suppressed inflammation, alleviating the accumulation of TREM2-expressing cells in the brain. It also mitigated glutamate levels and oxidative tissue damage and reduced brain levels of active caspases, indicative of apoptotic cell death. Thus, the oral administration of taxifolin had intracerebral pleiotropic neuroprotective effects on CAA through suppressing amyloid-β production and beneficially modulating proinflammatory microglial phenotypes.
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Author contributions: M.T. designed research; T.I. and S.S. performed research; T.I., S.S., M.T., H.Y., T.K., A.S., M.I., and N.S.-A. analyzed data; and T.I., S.S., M.T., M.I., and N.S.-A. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1901659116/-/DCSupplemental.
Published under the PNAS license.