Simvastatin ameliorate memory deficits and inflammation in clinical and mouse model of Alzheimer's disease via modulating the expression of miR-106b.

BACKGROUND

Alzheimer's disease (AD) as a neurodegenerative brain disorder is a devastating pathology leading to disastrous cognitive impairments and dementia, and several studies have shown that AD is closely related to the inflammation, so anti-inflammatory treatment may provide therapeutic benefits. In this study, the effect of simvastatin on inflammation was investigated and the underlying mechanisms were explored.

METHODS

First, we tested the effect of simvastatin on AD in clinical research. The fasting venous blood was collected in order to evaluate the levels of interleukin-6 (IL-6), interleukine-1 beta (IL-1β), antichymotrypsin (ACT) and human tumor necrosis factor α (TNF-α), which were measured with the enzyme-linked immunosorbent assay (ELISA) kits. Amyloid-β (Aβ), amyloid-β precursor protein (APP) and β-site APP-cleaving enzyme 1(BACE1) were tested by western blotting. Second, we used an APPswe/PS1E9 (APP/PS1) double transgenic mice to evaluate the amelioration ability of simvastatin against the memory impairment in vivo. Spatial learning and memory of mice were investigated by the Morris water maze test (MWM). The mRNA of inflammatory cytokines were measured using real-time PCR. Third, the phospho-proteome profile of SH-SY5Y human neuroblastoma cells treated with simvastatin was used to investigate the possible mechanisms.

RESULTS

The results showed that simvastatin ameliorated the memory deficits both in clinical AD patients and animal model of AD. Simvastatin could reduce the mRNA expression of inflammatory cytokines and mediators, suppress the apoptosis of neural stem cells and improve the survival rate of neurons. Moreover, long non-coding RNA (lnc RNA) n336694 and miR-106b was overexpressed in APP/PS1 mice brain tissues, the relationship between lnc RNA n336694 and miR-106b was explored using the method of Target Scan bioinformatics predictions, the results revealed that miR-106b might be a potential target of lnc RNA n336694. Furthermore, miR-106b mediated apoptosis in SH-SY5Y cell and simvastatin could suppressed this process.

CONCLUSION

Our results suggested that simvastatin could be of benefit in preventing the progression of AD and expected to be potentially used as a lead drug for further anti-AD treatment.