Genetic and environmental factors affecting Alzheimer's disease pathogenic mechanism: the role of sirtuins

Polito, Letizia (2012). Genetic and environmental factors affecting Alzheimer's disease pathogenic mechanism: the role of sirtuins. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000eebf

Abstract

Alzheimer's disease (AD) is the leading cause of senile dementia and the current lack of effective treatments provides a strong incentive for an improved therapeutic strategy. In particular, non-pharmacological treatments, such as calorie restriction (CR), were shown to be useful in delaying or preventing AD onset. This has given insight into the molecular pathways involved. Sirtuins (SIRT1-7) are evolutionary conserved enzymes that modulate life expectancy in simple organisms. In mammals, sirtuins are involved in pathways linked to age-related diseases, such as AD. In particular, they seem to be the molecular effectors of some beneficial effects mediated by external stimuli such as CR and physical activity. This thesis aims at investigating, for the first time, the involvement of all 7 sirtuins in AD. The relevance of sirtuin gene variation to AD risk was assessed by a combined mutation screening and case-control genetic study design. Sirtuin expression levels were also assessed in a transgenic mouse model of AD (APP23 mice) and within the application of a non-pharmacological approach (environmental enrichment-EE). Finally, the possible role of SIRT1 in AD pathogenesis was better elucidated through in vitro studies. Overall, in vitro studies confirmed the neuroprotective role of SIRT1 activator resveratrol in etiopathological contexts related to AD. Moreover, genetic studies have highlighted SIRT2 could be involved in modulating AD etiology. In particular, a common polymorphism in SIRT2 could be a weak genetic risk factor for AD. Finally, in vivo studies confirmed the beneficial effects of an EE protocol in delaying AD onset. However, despite sirtuin involvement in other environmental paradigms, no apparent modulation was registered under EE.

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