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.

These findings indicate that the reduced level of SIRT1 in the brains of patients with AD may be related to the decline in SOD-1 and neuropathological changes of this disorder.

To reveal the molecular mechanism of deficit in learning and memory induced by chronic fluorosis, the expression of muscarinic acetylcholine receptors (mAChRs) and oxidative stress were investigated. Sixty Sprague-Dawley (SD) rats were divided randomly into two groups (30 cases in each), i.e., the control group (<0.5 ppm fluoride in drinking water) and the fluoride group (50 ppm fluoride) for 10 months of treatment. The pups born from SD mothers with or without chronic fluorosis were selected at postnatal days 1, 7, 14, 21 and 28 for experiments (10 for each age). Spatial learning and memory were evaluated by Morris water maze test. The expressions of M1 and M3 mAChRs at the protein and mRNA levels were determined by Western blotting and real-time PCR, respectively. In addition, the contents of (·)OH, H2O2, O2(·-) and malondialdehyde (MDA), and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in brains were quantitated by biochemical methods. Our results showed that as compared to controls, the abilities of learning and memory were declined in the adult rats and the offspring rats of postnatal day 28 in the fluoride groups; the expressions of both M1 and M3 mAChRs were significantly reduced at protein and mRNA levels; and the levels of (·)OH, H2O2, O2(·-) and MDA were significantly increased, while the activities of SOD and GSH-Px decreased. Interestingly, the decreased protein levels of M1 and M3 mAChRs were significantly correlated with the deficits of learning and memory and high level of oxidative stress induced by chronic fluorosis. Our results suggest that the mechanism for the deficits in learning and memory of rats with chronic fluorosis may be associated with the decreased expressions of M1 and M3 in mAChRs, in which the changes in the receptors might be the result of the high level of oxidative stress occurring in the disease.

Ligands of nicotinic acetylcholine receptors (nAChRs) are widely considered as potential therapeutic agents. The present study used primary hippocampus cells and APPswe/PSEN1dE9 double-transgenic mice models to study the possible therapeutic effect and underlying mechanism of the specific activation of α7 nAChR by PNU-282987 in the pathogenesis of Alzheimer's disease. The results indicated that activation of α7 nAChR attenuated the Aβinduced cell apoptosis, decreased the deposition of Aβ, increased the expression of synaptic-associated proteins, and maintained synaptic morphology. Furthermore, in the APP/PS1_DT mice model, activation of α7 nAChR attenuated Aβ-induced synaptic loss, reduced the deposition of Aβ in the hippocampus, maintained the integral structure of hippocampus-derived synapse, and activated the calmodulin (CaM)-calmodulin-dependent protein kinase II (CaMKII)-cAMP response element-binding protein signaling pathway by upregulation of its key signaling proteins. In addition, activation of α7 nAChR improved the learning and memory abilities of the APP/PS1_DT mice. Collectively, the activation of α7 nAChR by PNU-282987 attenuated the toxic effect of Aβ in vivo and in vitro, which including reduced deposition of Aβ in the hippocampus, maintained synaptic morphology by partially reversing the expression levels of synaptic-associated proteins, activation of the Ca 2+ signaling pathway, and improvement of the cognitive abilities of APP/PS1_DT mice.

No abstract