Sirtuins in Cognitive Ageing and Alzheimer's Disease

Nady Braidy; Tharusha Jayasena; Anne Poljak; Perminder S. Sachdev


Curr Opin Psychiatry. 2012;25(3):226-230. 

In This Article

SIRT1-mediated Attenuation of Aβ and Tau Pathology

The pathogenesis of Alzheimer's disease is characterized by marked increase in oxidative stress and mitochondrial damage, significant neuroinflammation, increased calcium signalling, amyloid-β (Aβ) oligomerization and fibrillation, and tau hyperphosphorylation.[25,26] Evidence regarding the neuroprotective effects of sirtuins in Alzheimer's disease stems from current research focussing on SIRT1 [20•]. In-vitro activation of SIRT1 by either NAD+ or resveratrol can significantly reduce the levels of oligomerized Aβ by switching the processing of amyloid precursor protein (APP) by increasing the production of alpha-secretase.[25,26] Moreover, overexpression of SIRT1 also prevented the activation of microglia by fibrillar Aβ, therefore reducing the release of neurotoxic chemokines, cytokines and nitric oxide from activated microglia through inhibition of the nuclear factor-kappaB (NFκB) signalling pathway.[27]

Recently, a double transgenic mouse model overexpressing both APP and SIRT1 showed reduced Aβ formation compared with APP transgenic mice only. Moreover, increased Alzheimer's disease-like brain abnormalities and increased behavioural dysfunction have been observed in SIRT1-deficient APP mice.[17•] The antiamyloidogenic effects of SIRT1 are mediated by the direct activation of the alpha-secretase gene ADAM10 by binding to its promoter. SIRT1-induced activation of ADAM10 can also activate the Notch signalling pathway, by cleavage of the Notch receptor, which promotes neuronal repair. This can free an intracellular Notch domain that forms a transcription complex that upregulates the transcription of genes necessary for the promotion of neurogenesis.[28••]

Leptin is a pleiotropic hormone that is released from adipocytes. Recently, leptin has been shown to modulate Alzheimer's disease pathology by activation of the AMP-activated protein kinase (AMPK).[29•] Greco et al.[29•] recently showed that leptin can boost cellular metabolism by activating AMPK and SIRT1 to reduce Aβ and tau phosphorylation. Considering the significance of leptin deficiency in contributing to the neuronal imbalance observed in Alzheimer's disease, there has been renewed interest in the use of leptin as a legitimate treatment for Alzheimer's disease.

As well, injection of resveratrol in P25 transgenic mice showed a reduction in hippocampal degeneration, improved cognitive function and lowered acetylation levels of SIRT1-binding proteins such as p53.[30] Overexpression of SIRT1 using a lentivirus also improved hippocampal integrity, mimicking the neuroprotective effects of resveratrol injections.

PET images using the Pittsburgh compound B have shown that Aβ deposition is colocalized with regions of the brain that metabolize glucose by aerobic glycolysis in normal, young brains.[31•] These regions are dependent on the optimal conversion of glucose 6-phosphate to pyruvate, which is essential for the proliferation of neuronal cells and serves as a rapid source of energy production.[32] Aerobic glycolysis is also associated with altered NAD+ recycling. As SIRT1 activity requires adequate levels of NAD+, it is not surprising that the development of Aβ pathology might be related to alterations in aerobic glycolysis in the Alzheimer's disease brain, inhibiting SIRT1 activity by lowering the NAD/NADH ratio, and therefore shifting APP processing to promote amyloidogenic activity.[33,34]


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