Sirtuin modulators control reactive gliosis in an in vitro model of Alzheimer's disease (original) (raw)
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Therapeutic role of sirtuins in neurodegenerative disease
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2008
The sirtuins are a family of enzymes which control diverse and vital cellular functions, including metabolism and aging. Manipulations of sirtuin activities cause activation of anti-apoptotic, anti-inflammatory, anti-stress responses, and the modulation of aggregation of proteins involved in neurodegenerative disorders. Recently, sirtuins were found to be disease modifiers in various models of neurodegeneration. However, almost in all instances, the exact mechanisms of neuroprotection remain elusive.
Neuroprotective Mechanisms of Resveratrol in Alzheimer's Disease: Role of SIRT1
Alzheimer's disease (AD) is a progressive and neurodegenerative disorder of the cortex and hippocampus, which eventually leads to cognitive impairment. Although the etiology of AD remains unclear, the presence of β-amyloid (Aβ) peptides in these learning and memory regions is a hallmark of AD. Therefore, the inhibition of Aβ peptide aggregation has been considered the primary therapeutic strategy for AD treatment. Many studies have shown that resveratrol has antioxidant, anti-inflammatory, and neuroprotective properties and can decrease the toxicity and aggregation of Aβ peptides in the hippocampus of AD patients, promote neurogenesis, and prevent hippocampal damage. In addition, the antioxidant activity of resveratrol plays an important role in neuronal differentiation through the activation of silent information regulator-1 (SIRT1). SIRT1 plays a vital role in the growth and differentiation of neurons and prevents the apoptotic death of these neurons by deacetylating and repressing p53 activity; however, the exact mechanisms remain unclear. Resveratrol also has anti-inflammatory effects as it suppresses M1 microglia activation, which is involved in the initiation of neurodegeneration, and promotes Th2 responses by increasing anti-inflammatory cytokines and SIRT1 expression. This review will focus on the antioxidant and anti-inflammatory neuroprotective effects of resveratrol, specifically on its role in SIRT1 and the association with AD pathophysiology.
Title: Therapeutic role of sirtuins in neurodegenerative disease and their modulation by polyphenols
Searching for effective therapeutic agents to prevent neurodegeneration is a challenging task due to the growing list of neurodegenerative disorders associated with a multitude of interrelated pathways. The induction and inhibition of several different signaling pathways has been shown to slow down and/or attenuate neurodegeneration and decline in cognition and locomotor function. Among these signaling pathways, a new class of enzymes known as sirtuins or silent information regulators of gene transcription has been shown to play important regulatory roles in the ageing process. SIRT1, a nuclear sirtuin, has received particular interest due to its role as a deacetylase for several metabolic and signaling proteins involved in stress response, apoptosis, mitochondrial function, self-renewal, and neuroprotection. A new strategy to treat neurodegenerative diseases is targeted therapy. In this paper, we reviewed up-to-date findings regarding the targeting of SIRT1 by polyphenolic compounds, as a new approach in the search for novel, safe and effective treatments for neurodegenerative diseases.
CNS SIRT3 Expression Is Altered by Reactive Oxygen Species and in Alzheimer’s Disease
PLoS ONE, 2012
Progressive mitochondrial dysfunction contributes to neuronal degeneration in age-mediated disease. An essential regulator of mitochondrial function is the deacetylase, sirtuin 3 (SIRT3). Here we investigate a role for CNS Sirt3 in mitochondrial responses to reactive oxygen species (ROS)-and Alzheimer's disease (AD)-mediated stress. Pharmacological augmentation of mitochondrial ROS increases Sirt3 expression in primary hippocampal culture with SIRT3 over-expression being neuroprotective. Furthermore, Sirt3 expression mirrors spatiotemporal deposition of b-amyloid in an AD mouse model and is also upregulated in AD patient temporal neocortex. Thus, our data suggest a role for SIRT3 in mechanisms sensing and tackling ROS-and AD-mediated mitochondrial stress.
Current Neurovascular Research, 2009
One of the current problems in medicine research is the development of safe drugs for the treatment of neurological disorders. Furthermore, there is a close relationship between the process of aging and the appearance of neurological disorders, particularly Parkinson's disease and Alzheimer's disease. Therefore, an ideal compound would have two characteristics: neuroprotective action and an anti-aging effect. The natural compound resveratrol is a suitable candidate for this purpose due to its low toxicity and antioxidant properties. In addition, recent research has shown that it has an anti-aging effect in rat, yeast, Caenorhabditis elegans, and Drosophila, although the mechanism involved in this process remains to be clarified. One hypothesis is that by activating Sirtuin 1, resveratrol modulates the activity of numerous proteins, including peroxisome proliferator-activated receptor coactivator-1 (PGC-1 alpha), the FOXO family, Akt (protein kinase B) and nuclear factor-(NF ). This review summarises recent research on the molecular mechanisms through which resveratrol might exert its therapeutic effects via the interaction with Sirtuin 1, as well as other targets. In addition, we discuss the possibility of using resveratrol in the treatment of neurodegenerative diseases.
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2010
Sirt1, a mammalian member of the sirtuin gene family, holds great potential for promoting longevity, preventing against disease and increasing cell survival. For example, studies suggest that the beneficial impact of caloric restriction in promoting longevity and cellular function may be mediated, in part, by Sirt1 through mechanisms involving PGC-1α, which plays important role in the regulation of cellular metabolism and inflammatory and antioxidant responses. Sirt1 may also interfere with mechanisms implicated in pathological disorders. We will present recent evidence indicating that Sirt1 may protect against Alzheimer's disease by interfering with the generation of β-amyloid peptides. We will discuss Sirt1 as a potential novel target, in addition to the development of Sirt1 activators for the prevention and treatment of Alzheimer's disease.
Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders
Neurochemical research, 2016
Sirtuins (SIRT1-SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD(+) levels and thus on the cellular metabolic status. SIRTs regulate energy metabolism and mitochondrial function. They orchestrate the stress response and damage repair. Through these functions sirtuins modulate the course of aging and affect neurodegenerative diseases. SIRTSs interact with multiple signaling proteins, transcription factors (TFs) and poly(ADP-ribose) polymerases (PARPs) another class of NAD(+)-dependent post-translational protein modifiers. The cross-talk between SIRTs TFs and PARPs is a highly promising research target in a number of brain pathologies. This review describes updated results on sirtuins in brain aging/neurodegeneration. It focuses on SIRT1 but also on the roles of mitochondrial SIRTs (SIRT3, 4, 5) and on SIRT6 and SIRT2 localized in the nucleus and in cytosol, respectively. The involvement of SIRTs in regulation of insulin-like growth factor signaling in the ...