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-ß Peptide.

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-ß peptide (AßOs). 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 AßOs (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 AßOs. 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.

Protection against the Neurotoxic Effects of ß-Amyloid Peptide on Cultured Neuronal Cells by Lovastatin Involves Elevated Expression of α7 Nicotinic Acetylcholine Receptors and Activating Phosphorylation of Protein Kinases.

The treatment of neurodegenerative diseases with statins has drawn increasing attention, but the related molecular mechanisms remain elusive. To examine the pleiotropic cholesterol-independent effects of statins in connection with the treatment of Alzheimer disease, we probed the influence of lovastatin on the metabolism of amyloid precursor protein (APP), expression of nicotinic acetylcholine receptors (nAChRs), and activity of mitogen-activated protein kinase (MAPK) in primary cultured neurons and SH-SY5Y cells overexpressing human APP670/671. Lovastatin attenuated the neurotoxic effects of ß-amyloid peptide (Aß) and affected the metabolism of APP, reducing levels of Aß1 to Aß42 and ß-site amyloid precursor protein-cleaving enzyme 1; enhancing those of αAPP, disintegrin metalloproteinase domain-containing protein 10, and ß-site amyloid precursor protein-cleaving enzyme 2; and up-regulating expression of α7 nAChR and stimulating phosphorylation of extracellular signal-regulated kinase (ERK)1/2. Interestingly, methyllycaconitine, an antagonist of α7 nAChR, attenuated this effect on αAPP, but not on phospho-ERK1/2; whereas U0126, an inhibitor of MAPK/ERK kinase/ERK, blocked both the elevated expression of α7 nAChR and enhanced secretion of αAPP. Our findings indicate that lovastatin up-regulates expression of α7 nAChR by a mechanism involving activation of the MAPK/ERK pathway, which may result in diminished production of Aß.