Abstract
Among neurodegenerative disorders, Alzheimer’s disease (AD) represents the most common cause of dementia in the elderly. Several genetic and environmental factors have been identified; however, aging represents the most important risk factor in the development of AD. To date, no effective treatments to prevent or slow this dementia are available. Sirtuins (SIRTs) are a family of NAD+-dependent enzymes, implicated in the control of a variety of biological processes that have the potential to modulate neurodegeneration. Here we tested the hypothesis that activation of SIRT1 or inhibition of SIRT2 would prevent reactive gliosis which is considered one of the most important hallmark of AD. Primary rat astrocytes were activated with beta amyloid 1-42 (Aβ 1-42) and treated with resveratrol (RSV) or AGK-2, a SIRT1 activator and a SIRT2-selective inhibitor, respectively. Results showed that both RSV and AGK-2 were able to reduce astrocyte activation as well as the production of pro-inflammatory mediators. These data disclose novel findings about the therapeutic potential of SIRT modulators, and suggest novel strategies for AD treatment.
Highlights
Alzheimer’s disease (AD) represents one of the major health concern and it is a research priority since there is a pressing need to develop new agents to prevent or treat it
The purpose of this study was to assess the efficacy of RSV, a well-known SIRT1 activator, and AGK-2, a potent SIRT2-selective inhibitor, in counteracting reactive gliosis, considered one of the characteristic phenomena occurring in AD
In the last years researchers focused their attention on the role of reactive gliosis in the onset and progression of many neurodegenerative disorders, including AD
Summary
Alzheimer’s disease (AD) represents one of the major health concern and it is a research priority since there is a pressing need to develop new agents to prevent or treat it. Senile plaques and neurofibrillary tangles (which are considered the more characteristic hallmarks of AD) co-localize with activated astrocytes, suggesting for these cells a key role in the pathogenesis of AD (Meda et al, 2001; Craft et al, 2006) Along this line, in several experimental models it has been demonstrated that Aβ peptide fragments markedly alter astrocytes functions. Over-release of pro-inflammatory cytokines by glia cells causes neuronal dysfunction and loss of synapses, which correlates with memory decline. These phenomena are believed to precede neuronal death. Research focused on developing therapeutic strategies directed at controlling the prolonged and uncontrolled glia activation should be encouraged
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