Distinct Patterns of Sirtuin Expression During Progression of Alzheimer’s Disease

Neuromolecular medicine (Impact Factor: 3.68). 01/2014; 16(2). DOI: 10.1007/s12017-014-8288-8
Source: PubMed


Aging is one of the major risk factors for Alzheimer's disease (AD). Sirtuins are associated with prolonged life span. To examine whether the expression levels of sirtuins associate with the progression of AD or not, we performed a comparative immunoblotting and immunohistochemical study of SIRT1, 3, and 5 in the entorhinal cortex and hippocampal subregions and white matter in 45 cases grouped according to Braak and Braak stages of neurofibrillary degeneration. In addition, we compared the expression levels with the local load of tau and amyloid-beta deposits, evaluated using morphometry. Our study revealed that (1) the neuronal subcellular redistribution of SIRT1 parallels the decrease in its expression, suggesting stepwise loss of neuroprotection dependent on the neuronal population; (2) in contrast to SIRT1 and 3, expression of SIRT5 increases during the progression of AD; (3) which might be related to its appearance in activated microglial cells. The complex patterns of the expression of sirtuins in relation to tissue damage should be taken into account when searching for therapies interacting with sirtuins.

32 Reads
  • Source
    • "As such, it is not unlikely that the association of TREM2 with AD and other neurodegenerative conditions is linked to alterations in the regulation of local melatonin and its autocrine and paracrine actions. Similarly, miR-34a may be important to the antagonistic interactions of NF-KB and sirtuin-1 [209], and therefore linking alterations in the regulation of the melatoninergic pathways to the decrease in the longevity protein, sirtuin-1, over the course of AD [210]. Melatonin increases sirtuin-1 [211], which significantly improves mitochondrial functioning in AD models [212], as well as decreasing microglia reactivity to amyloid-β [213]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The utilization of tryptophan for the synthesis of serotonin, allows some of this serotonin to be broken down into N-acetylserotonin (NAS) and melatonin, forming the melatoninergic pathways. Many of the changes and susceptibility factors associated with Alzheimer's disease (AD) regulate, and can be regulated by, the melatoninergic pathways. Melatonin is well known for its night-time release by the pineal gland, which contributes to entraining the circadian rhythm. Decreased pineal melatonin and disruption of the circadian rhythm is common in AD, with melatonin supplementation affording significant protection against cognitive deficits and circadian disruption in most clinical trials. Melatonin is also a significant regulator of the immune system, where its effects afford protection against immuno-senescence and associated alterations in immune responses in AD patients. Being a significant antioxidant, anti-inflammatory and optimizer of mitochondrial functioning, melatonin has many benefits in AD. Recent data shows that melatonin is produced by many other, if not all, human cells, including astrocytes and immune cells. The release of melatonin by these cells allows for autocrine and paracrine effects that decrease the reactivity of glia and immune cells. Given the role of heightened glia and immune cell reactivity in AD, local melatonin synthesis by these cells is a significant pharmaceutical target. NAS may be more than simply the immediate precursor of melatonin. NAS is also a powerful antioxidant as well as being a brain derived neurotrophic factor (BDNF) mimic. Given the general protective effects of BDNF and its decrease in AD, NAS is likely to afford protection in AD patients, with effects not necessarily the same as those of melatonin. In this chapter, we review the role of the melatoninergic pathways in AD, highlighting its usefulness in managing this devastating, and still poorly treated, disease.
    01/2015: chapter Melatoninergic Pathways in Alzheimer's Disease: pages 3-49;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Currently, it is unclear whether a neuron that undergoes viral reactivation and produces infectious particles survives and resumes latency or is killed, which is intriguing even if still unanswered. Previous reports have shown that herpes simplex virus type 1 (HSV-1) inhibits apoptosis during early infection, but is pro-apoptotic during productive infection. Taking in consideration that the stress sensors AMPK and Sirt1 are involved in neuronal survival and neuroprotection, we hypothesized that HSV-1 could activate the AMPK/Sirt1 axis as a strategy to establish latency through inhibition of apoptosis and restoration of the energy status. These effects could be accomplished through deacetylation of pro-apoptotic protein p53 and regulation of the master regulator of mitochondrial biogenesis and function PGC-1α and its target gene TFAM. Accordingly, we evaluated the AMPK/Sirt1 axis and its targets p53, PGC-1α, and acetyl CoA carboxylase in mice neuronal cultures infected with HSV-1 by western blot, RT-qPCR, and immunofluorescence analyses. Herein, we show that HSV-1 differentially modulates the AMPK/Sirt1 axis during the course of infection. In fact, during early infection (2 hpi) activated AMPK (p-AMPK) was down-regulated, but thereafter recovered gradually. In contrast, the levels of acetylated-p53 increased during the first hours post infection, but afterwards were reduced in parallel with the activation of Sirt1. However, acetylated-p53 peaked again at 18 hpi during productive infection, suggesting an activation of apoptosis. Strikingly, acetylated-p53, Sirt1, and p-AMPK apparently translocate from the nucleus to the cytoplasm after 4 hpi, where they accumulate in discrete foci in the perinuclear region. These results suggest that HSV-1 modulates the AMPK/Sirt1 axis differentially during the course of infection interfering with pro-apoptotic signaling and regulating mitochondrial biogenesis.
    Journal of Alzheimer's disease: JAD 05/2014; 42(1). DOI:10.3233/JAD-140237 · 4.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Modification of the histone proteins associated with DNA is an important process in the epigenetic regulation of DNA structure and function. There are several known modifications to histones, including methylation, acetylation, and phosphorylation, and a range of factors influence each of these. Histone deacetylases (HDACs) remove the acetyl group from lysine residues within a range of proteins, including transcription factors and histones. Whilst this means that their influence on cellular processes is more complex and far-reaching than histone modifications alone, their predominant function appears to relate to histones; through deacetylation of lysine residues they can influence expression of genes encoded by DNA linked to the histone molecule. HDAC inhibitors in turn regulate the activity of HDACs, and have been widely used as therapeutics in psychiatry and neurology, in which a number of adverse outcomes are associated with aberrant HDAC function. More recently, dietary HDAC inhibitors have been shown to have a regulatory effect similar to that of pharmacological HDAC inhibitors without the possible side-effects. Here, we discuss a number of dietary HDAC inhibitors, and how they may have therapeutic potential in the context of a whole food.
    Nutrients 10/2014; 6(10):4273-4301. DOI:10.3390/nu6104273 · 3.27 Impact Factor
Show more