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Multifunction of myricetin on Aβ: Neuroprotection via a conformational change of Aβ and reduction of Aβ via the interference of secretases
Author(s) -
Shimmyo Yoshiari,
Kihara Takeshi,
Akaike Akinori,
Niidome Tetsuhiro,
Sugimoto Hachiro
Publication year - 2007
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21476
Subject(s) - myricetin , chemistry , neurotoxicity , biophysics , pharmacology , oxidative stress , neuroprotection , förster resonance energy transfer , biochemistry , amyloid beta , antioxidant , flavonoid , biology , toxicity , fluorescence , kaempferol , peptide , physics , organic chemistry , quantum mechanics
Myricetin (3,3′,4′,5,5′,7‐hexahydroxyflavone) is classified as a flavonoid with strong antioxidant effects. Oxidative stress plays a key role in various neurological diseases such as ischemia and Alzheimer's disease (AD). To elucidate whether myricetin could counter the progress of AD, we examined the effects of myricetin on neurotoxicity induced by β‐amyloid (Aβ), a component of senile plaques in the AD brain. We found that cultured rat primary cortical neurons treated for 48 hr with Aβ1–42 (1 μM) induced significant neuronal injury. Conformationally altered Aβ1–42 caused apoptotic changes, such as nuclear fragmentation, as shown by DAPI staining. Pre‐ and simultaneous administration of myricetin and Aβ1–42 reduced Aβ neurotoxicity in a concentration‐dependent manner. By using circular dichroism spectroscopy and a thioflavin T binding assay, we show that myricetin (10 μM, 48 hr) prevented structural changes in Aβ1–42 from a random coil to a β‐sheet‐rich structure. Aβ1–42‐induced apoptotic changes and caspase‐3 activation were reduced by myricetin treatment. Furthermore, we determined that administration of myricetin significantly decreased Aβ1–40 and Aβ1–42 levels in culture media. These effects were based on two mechanisms: the activation and up‐regulation of α‐secretase (ADAM10) protein levels as indicated by fluorescence resonance energy transfer (FRET) assay and immunoblot analysis and the direct binding and inhibition of β‐secretase (BACE‐1) indicated by cell‐free FRET assays. Evidently, myricetin has multiple functions to counter the progress of AD by the reduction of Aβ production and the detoxification of Aβ through a structural change. © 2007 Wiley‐Liss, Inc.