Stimulation of SIRT1 Attenuates the Level of Oxidative Stress in the Brains of APP/PS1 Double Transgenic Mice and in Primary Neurons Exposed to Oligomers of the Amyloid-β Peptide

Abstract

In the study, we examined whether the silent information regulator 1 (SIRT1) can attenuate oxidative stress in the brains of mice carrying the APP/PS1 double mutation and/or in primary neonatal rat neurons exposed to oligomers of amyloid-β peptide (AβOs). Starting at 4 or 8 months of age, the transgenic mice were treated with resveratrol (RSV, a stimulator of SIRT1) or suramin (an inhibitor) (each 20 mg/kg BW/day) for two months. The primary neurons were exposed to AβOs (0.5 μM) for 48 h and thereafter RSV (20 μM) or suramin (300 mg/ml) for 24 h. Cell viability was assessed by the CCK-8 assay; SIRT1 protein and mRNA determined by western blotting and real-time PCR, respectively; senile plaques examined immunohistochemically; ROS monitored by flow cytometry; and the contents of OH-, H2O2, O2·-, and MDA, and the activities of SOD and GSH-Px measured by standard biochemical procedures. In comparison to wild-type mice or untreated primary neurons, the expression of SIRT1 was significantly lower in the brains of APP/PS1 mice or neurons exposed to AβOs. In these same systems, increased numbers of senile plaques and a high level of oxidative stress were apparent. Interestingly, these two latter changes were attenuated by treatment with RSV, but enhanced by suramin. These findings indicate that SIRT1 may be neuroprotective.

The neuroprotective effects of SIRT1 in mice carrying the APP/PS1 double-transgenic mutation and in SH-SY5Y cells over-expressing human APP670/671 may involve elevated levels of α7 nicotinic acetylcholine receptors

“…Recent research also shows that activation of SIRT1 protects neurons against Aβ1-42-induced disruption of spatial learning, memory, and synaptic plasticity and counteracts the reduction of SIRT1 expression in hippocampus of rats [23]. Moreover, our own findings reveal that activation of SIRT1 attenuates the oxidative stress caused by amyloid-peptide [24]. These observations identify SIRT1 as a promising therapeutic target for overcoming neurodegeneration.…”

“…B6.Cg-Tg (APPswe, PSEN 1dE9) mice with an 85Dbo/Mmjax background and strain-matched wildtype (WT) mice were purchased from Shanghai Nanfang Biological Technology Development Co., Ltd. APP/PS1 mice were generated and identified as described previously [24], which is a familial model of AD and represents 1% -3% of the disease (96% is sporadic). At four months of age, 27 double-transgenic mice, and 9 age-and gender-matched WT mice were divided randomly into four groups (n=9/per gourp) as follows: the WT group, APP/PS1 group, RSV-treated group and suramin-treated group.…”

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

“…A recent investigation by our own group16 revealed that in comparison to wild-type mice and untreated primary neurons, expression of SIRT1 is significantly lower both in the brains of APP/PS1 mice and neurons exposed to Aβ. In these same systems, increased numbers of senile plaques and a high level of oxidative stress are apparent, changes than can be attenuated by resveratrol (a stimulator of SIRT1), but enhanced by suramin (an inhibitor of SIRT1).…”

Exposure to fluoride aggravates the impairment in learning and memory and neuropathological lesions in mice carrying the APP/PS1 double-transgenic mutation

“…Extracellular senile plaques containing β-amyloid peptide (Aβ), intra-neuronal neurofibrillary tangles, brain atrophy, and loss of neurons are the neuropathological hallmarks of this disease [3,4]. Clear evidence indicates that accumulation of Aβ, a 4-kDa polypeptide formed by proteolytic cleavage of amyloid precursor protein (APP) by βand γ-secretases, is a primary pathogenic event [5,6], leading to synaptic and neuronal loss, oxidative damage, and multiple inflammatory responses [7][8][9].…”