Lovastatin stimulates up-regulation of α7 nicotinic receptors in cultured neurons without cholesterol dependency, a mechanism involving production of the α-form of secreted amyloid precursor protein
✍ Scribed by Jin Xiu; Agneta Nordberg; Ke-Ren Shan; Wen-Feng Yu; Jerker M. Olsson; Tomas Nordman; Malahat Mousavi; Zhi-Zhong Guan
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 455 KB
- Volume
- 82
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
The cholesterol-lowering drug lovastatin enhances the secretion of the a-secretase cleavage product of amyloid precursor protein (APP). To investigate whether this effect is mediated via activation of a7 nicotinic acetylcholine receptors (nAChRs), we treated SH-SY5Y cells and PC12 cells with lovastatin and measured the levels of a7 nAChRs, the a-form of secreted APP (aAPPs), and lovastatin-related lipids, including cholesterol and ubiquinone. The results showed that low concentrations of lovastatin significantly induced up-regulation of a7 nAChRs. No effects of lovastatin were observed on a3containing nAChRs, muscarinic receptors, or N-methyl-D-aspartate receptors. aAPPs levels increased in the culture medium of cells treated with lovastatin, whereas no change in whole APP was observed. The increase in aAPPs was inhibited by prior exposure of these cells to a-bungarotoxin, an antagonist of a7 nAChRs. The concentrations of lovastatin used in the study did not change the cholesterol content, but high doses can decrease the levels of ubiquinone and cell viability. These results indicate that lovastatin may play a neuronal role that is cholesterol independent. We also show that the up-regulation of a7 nAChRs stimulated by lovastatin is involved in a mechanism that enhances production of aAPPs during APP processing.