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

ArticleinNeuromolecular medicine 16(2) · January 2014with42 Reads
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.
    • "These data are in agreement with a study by Lutz and collaborators, which found a loss of SIRT-1 during AD progression by the Braak staging system of neurofibrillary degeneration. Alongside the decrease in SIRT-1 expression, which is inversely correlated with tau and amyloid protein accumulation, they also observed that the loss of SIRT-1 is dependent on the neuronal population, after analyzing different brain subregions [71]. Concerning the involvement of COX-2 and SIRT-1 in neuroinflammation, it is clear from the present data that SIRT-1 expression is inversely proportional to the expression of COX-2 (Fig. 5). "
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    • "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]. "
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    • "For example, a recent study of patients in different stages of neurofibrillary degeneration showed that expression of SIRT1 is decreased and redistributed in neuron cells during AD progression which suggests stepwise loss of neuroprotection. However, in contrast to SIRT1, the expression of SIRT5 increases during the progression of AD [87]. In fact, SIRT5 has only recently been discovered to possess broader deacylase activity, and functions primarily as a lysine demalonylase and desuccinylase [88,89]. "
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