Multifunction of myricetin on A beta: neuroprotection via a conformational change of A beta and reduction of A beta via the interference of secretases.
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 beta-amyloid (A beta), a component of senile plaques in the AD brain. We found that cultured rat primary cortical neurons treated for 48 hr with A beta1-42 (1 microM) induced significant neuronal injury. Conformationally altered A beta1-42 caused apoptotic changes, such as nuclear fragmentation, as shown by DAPI staining. Pre- and simultaneous administration of myricetin and A beta1-42 reduced A beta neurotoxicity in a concentration-dependent manner. By using circular dichroism spectroscopy and a thioflavin T binding assay, we show that myricetin (10 microM, 48 hr) prevented structural changes in A beta1-42 from a random coil to a beta-sheet-rich structure. A beta1-42-induced apoptotic changes and caspase-3 activation were reduced by myricetin treatment. Furthermore, we determined that administration of myricetin significantly decreased A beta1-40 and A beta1-42 levels in culture media. These effects were based on two mechanisms: the activation and up-regulation of alpha-secretase (ADAM10) protein levels as indicated by fluorescence resonance energy transfer (FRET) assay and immunoblot analysis and the direct binding and inhibition of beta-secretase (BACE-1) indicated by cell-free FRET assays. Evidently, myricetin has multiple functions to counter the progress of AD by the reduction of A beta production and the detoxification of A beta through a structural change.
Shimmyo
Yoshiari
Y
Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Kihara
Takeshi
T
Akaike
Akinori
A
Niidome
Tetsuhiro
T
Sugimoto
Hachiro
H
D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002942:Circular Dichroism; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000494:pharmacology*; D007150:Immunohistochemistry; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017433:Protein Structure, Secondary / Q000187:drug effects; D051381:Rats
D016229:Amyloid beta-Peptides; D005419:Flavonoids; D018696:Neuroprotective Agents; C040015:myricetin; D053829:Amyloid Precursor Protein Secretases