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

Abstract

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.

Reduced expression of SIRT1 and SOD-1 and the correlation between these levels in various regions of the brains of patients with Alzheimer's disease

“…We found here that the IOD of SIRT1 or SOD-1 immunostaining in the temporal and frontal cortices, and hippocampus, but not the cerebellum, were both significantly correlated with the Braak stage, which supported by previous reports 37. Since the cortices and hippocampus, but not the cerebellum, are regions of the brains of patients with AD obviously affected,43 SIRT1 and/or SOD-1 may be involved in the pathology of AD.…”

“…SIRT1 is expressed at lowered levels in the brains of patients with AD, indicating that loss of this factor may play a key role in the pathogenesis and progression of AD 36. A previous study on brain tissue derived from individuals with AD found decreased protein expression of SIRT1 in the hippocampus during the progression of AD 37. Similar to our present findings, reduced expression of SIRT1 in the temporal and frontal cortices, and hippocampus was observed, but not cerebellum of patients with AD in comparison with the age-matched control groups.…”

Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease

“…Recently, it is reported that ROS originated from [4]. A recent study concluded that sirt3 expression is decreased during the progression of AD in human study [21]. Interestingly, sirt3 involves in ROS production and detoxification, in large part by targeting proteins that regulate intracellular antioxidant machinery [10].…”

Genomic integrity and the ageing brain

“…SIRT6 also facilitates chromatin opening at the site of DNA damage by recruiting sucrose nonfermenting protein 2 homologue (SNF2H; also known as SMARCA5) 137 , and it facilitates the recruitment of downstream factors, such as TP53BP1, BRCA1 and replication protein A (RPA) 137 . In Alzheimer disease, levels of different members of the sirtuin family are dysregulated 138,139 and it has been suggested that modulation of sirtuin levels or activity, through pharmacological innervation or calorie restriction, may offer new approaches to the prevention or treatment of neurodegenerative disorders. Collectively, these data suggest that the sirtuins, long associated with alterations in the rate of ageing, are also important in maintaining genomic integrity via their effects on the DNA repair process.…”