Resveratrol Promotes Clearance of Alzheimer's Disease Amyloid-β Peptides

Several epidemiological studies indicate that moderate consumption of wine is associated with a lower incidence of Alzheimer's disease. Wine is enriched in antioxidant compounds with potential neuroprotective activities. However, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in Alzheimer's disease brain remain to be clearly defined. Here we show that resveratrol (trans-3,4′,5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-β (Aβ) peptides produced from different cell lines. Resveratrol does not inhibit Aβ production, because it has no effect on the Aβ-producing enzymes β- and γ-secretases, but promotes instead intracellular degradation of Aβ via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of Aβ could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit β5. These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in Alzheimer's disease. Several epidemiological studies indicate that moderate consumption of wine is associated with a lower incidence of Alzheimer's disease. Wine is enriched in antioxidant compounds with potential neuroprotective activities. However, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in Alzheimer's disease brain remain to be clearly defined. Here we show that resveratrol (trans-3,4′,5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-β (Aβ) peptides produced from different cell lines. Resveratrol does not inhibit Aβ production, because it has no effect on the Aβ-producing enzymes β- and γ-secretases, but promotes instead intracellular degradation of Aβ via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of Aβ could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit β5. These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in Alzheimer's disease. Alzheimer's disease (AD) 2The abbreviations used are: ADAlzheimer's disease; Suc, succinylTMStrans-2,3′,4,5′-tetramethoxystilbeneALLNN-acetyl-LL-norleucinal-CHOELISAenzyme-linked immunosorbent assayECEendothelin-converting enzymeIDEinsulin-degrading enzyme; Aβ, amyloid-βAPPamyloid-β precursor proteinAMCamido-4-methylcoumarin; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycineWBWestern blottingIPimmunoprecipitationNEPneprilysinMOPS4-morpholinepropanesulfonic acidERendoplasmic reticulumsiRNAsmall interfering RNATBSTris-buffered saline; sAβ, secreted amyloid-βZbenzyloxycarbonyl is a progressive neurodegenerative disorder leading to the most common form of dementia. Compelling evidence supports the central role of Aβ in the pathogenesis of the disease (1Hardy J. Selkoe D.J. Science. 2002; 297: 353-356Crossref PubMed Scopus (11122) Google Scholar). Aβ is a core component of the senile plaque, a classical lesion found in the neocortex and hippocampus of AD brains, and excessive production of the highly insoluble 42-amino acid-long Aβ42 peptide is almost invariably observed in the presence of mutations in the three genes linked to early onset autosomal dominant familial forms of AD (2Tanzi R.E. Bertram L. Cell. 2005; 120: 545-555Abstract Full Text Full Text PDF PubMed Scopus (1508) Google Scholar). Alzheimer's disease; Suc, succinyl trans-2,3′,4,5′-tetramethoxystilbene N-acetyl-LL-norleucinal-CHO enzyme-linked immunosorbent assay endothelin-converting enzyme insulin-degrading enzyme; Aβ, amyloid-β amyloid-β precursor protein amido-4-methylcoumarin; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine Western blotting immunoprecipitation neprilysin 4-morpholinepropanesulfonic acid endoplasmic reticulum small interfering RNA Tris-buffered saline; sAβ, secreted amyloid-β benzyloxycarbonyl In the amyloidogenic pathway, the amyloid-β precursor protein (APP) is cleaved by the aspartic protease β-secretase/BACE1 to yield the membrane-anchored C-terminal fragments C99 and C89. C99 is then endoproteolyzed by the γ-secretase proteolytic complex to produce various Aβ peptides. The major cleavage takes place after Val-40 producing Aβ40. 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