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Alzheimer’s disease and SirT1: Could a red wine chemical point the way forward?
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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder which is the leading international cause of senile dementia. There is currently no cure for this disease. It is known that the E4 allele of the apolipoprotein E (ApoE4) is the major genetic risk factor for development of AD. It has also been recognised that a group of proteins known as sirtuins have protective effects against age-related diseases, including neurodegenerative diseases. One of these sirtuins is targeted for up-regulation and release from suppression by resveratrol, a polyphenol found mainly in grapes and red wine. In research published this week in The Proceedings of the National Academy of Sciences (PNAS), a possible link between APOE4 and SIRT1 has been uncovered that may offer future hope to ApoE4 gene carriers for new therapeutics.

In mammals there are seven sirtuins, SIRT1-7. They are NAD-dependent protein deacetylases with a variety of subcellular localisations and functions. SIRT1 has been shown to have a connection with lifespan extension linked to its role in calorie restriction. Research in the SAMP8 mouse model of age-related AD showed that dietary resveratrol supplements had positive effects including increased mean life expectancy and maximal life span and neuroprotective effects, including on the SIRT1 pro-survival pathway. It decreased the amyloid burden and reduced tau hyperphosphorylation. In vitro studies on PC12 cells have also shown that neurotoxicity of β-amyloid peptide 25-35 (Aβ(25-35)) could be ameliorated by addition of resveratrol to the culture medium via up-regulation of SIRT1 and consequent negative regulation of downstream signal molecule, ROCK1. Interestingly in the context of the present PNAS paper, SIRT1 has recently been shown to attenuate amyloidogenic processing of amyloid-β protein precursor (APP) both in vitro and in transgenic mouse models of Alzheimer's disease. SIRT1 increased production of the α-secretase enzyme via activation of the α-secretase gene ADAM10. Importantly, α-secretase mediates non-amyloidogenic cleavage of APP, thus its up-regulation would tend to reduce A beta species accumulation that is associated with AD. A beta species are associated with the sticky plaques which are a feature of AD.

In the current PNAS paper, researchers from the Buck Institute in the USA showed that both in cultured neural cells and in brain samples from patients with ApoE4 and AD, APOE4 reduced SIRT1 dramatically. Consistently with the studies linking SIRT1 to ADAM10 and non-amyloidogenic cleavage of APP, APOE4 favoured formation of the A beta peptide. Encouragingly, the PNAS paper showed that abnormalities associated with APOE4 and AD, including creation of phospho-tau and A beta peptide could be blocked by increasing SIRT1. Thus drug candidates that would have this effect would be promising future AD therapies, in particular for the high-risk ApoE4 gene carriers. Perhaps resveratrol or similar compounds may help point the way forward in AD therapeutic research.

Sources

BONDA, D.J. et al., 2011. The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations. Lancet Neurology, 10(3), pp. 275-279

BRAIDY, N. et al., 2012. Sirtuins in cognitive ageing and Alzheimer's disease. Current Opinion In Psychiatry, 25(3), pp. 226-230

DONMEZ, G. and OUTEIRO, T.F., 2013. SIRT1 and SIRT2: emerging targets in neurodegeneration. EMBO Molecular Medicine, 5(3), pp. 344-352

FENG, X. et al., 2013. Resveratrol inhibits β-amyloid-induced neuronal apoptosis through regulation of SIRT1-ROCK1 signaling pathway. Plos One, 8(3), pp. e59888-e59888

GUO, W. et al., 2011. Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling. Journal of neuroscience research, 89(11), pp. 1723-1736

KUMAR, R. et al., 2013. Sirtuin1: a promising serum protein marker for early detection of Alzheimer's disease. Plos One, 8(4), pp. e61560-e61560

PORQUET, D. et al., 2013. Dietary resveratrol prevents Alzheimer's markers and increases life span in SAMP8. Age (Dordrecht, Netherlands), 35(5), pp. 1851-1865

RAO, R. et al., 2013. Neuroprotective Sirtuin ratio reversed by ApoE4. PNAS, October 2013

Buck Institute for Age Research. "Major Alzheimer's risk factor linked to red wine target." ScienceDaily, 21 Oct. 2013. [Accessed 21 Oct. 2013]

http://www.buckinstitute.org/buck-news/m...ine-target [Accessed 21 Oct. 2013].
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