Lovastatin stimulates up-regulation of alpha7 nicotinic receptors in cultured neurons without cholesterol dependency, a mechanism involving production of the alpha-form of secreted amyloid precursor protein.
The cholesterol-lowering drug lovastatin enhances the secretion of the alpha-secretase cleavage product of amyloid precursor protein (APP). To investigate whether this effect is mediated via activation of alpha7 nicotinic acetylcholine receptors (nAChRs), we treated SH-SY5Y cells and PC12 cells with lovastatin and measured the levels of alpha7 nAChRs, the alpha-form of secreted APP (alphaAPPs), and lovastatin-related lipids, including cholesterol and ubiquinone. The results showed that low concentrations of lovastatin significantly induced up-regulation of alpha7 nAChRs. No effects of lovastatin were observed on alpha3-containing nAChRs, muscarinic receptors, or N-methyl-D-aspartate receptors. alphaAPPs levels increased in the culture medium of cells treated with lovastatin, whereas no change in whole APP was observed. The increase in alphaAPPs was inhibited by prior exposure of these cells to alpha-bungarotoxin, an antagonist of alpha7 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 alpha7 nAChRs stimulated by lovastatin is involved in a mechanism that enhances production of alphaAPPs during APP processing.
Xiu
Jin
J
Neurotec Department, Division of Molecular Neuropharmacology, Karolinska Institutet, Stockholm, Sweden.
Nordberg
Agneta
A
Shan
Ke-Ren
KR
Yu
Wen-Feng
WF
Olsson
Jerker M
JM
Nordman
Tomas
T
Mousavi
Malahat
M
Guan
Zhi-Zhong
ZZ
D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D002038:Bungarotoxins / Q000494:pharmacology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007554:Isotopes / Q000493:pharmacokinetics; D008148:Lovastatin / Q000494:pharmacology*; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000493:pharmacokinetics; D016716:PC12 Cells; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics; D011813:Quinuclidinyl Benzilate / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014451:Ubiquinone / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D016564:Amyloid beta-Protein Precursor; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007554:Isotopes; C409466:NR1 NMDA receptor; D018722:Nicotinic Agonists; D011725:Pyridines; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D014451:Ubiquinone; D011813:Quinuclidinyl Benzilate; D009538:Nicotine; D002784:Cholesterol; D008148:Lovastatin; C082748:epibatidine