Loss of nicotinic receptors induced by beta-amyloid peptides in PC12 cells: possible mechanism involving lipid peroxidation.
The mechanisms involved in the loss of nicotinic acetylcholine receptors (nAChRs), seen in brains of patients with Alzheimer's disease (AD) and in cultured cells treated by beta-amyloid peptides (A betas), remain elusive. We give results to show that lipid peroxidation induced directly by A beta might be involved in the deficits of nAChRs. In the study, PC12 cells were treated by addition of 5 microM of A beta(25-35) and A beta(1-40), respectively, with or without a antioxidant, vitamin E. Besides significantly decreased MTT (3-(4,5-dimethylthiazol-2-yl)-2,5,diphenyltetrazolium bromide) reduction, an increased lipid peroxidation was detected in the cells, but no protein oxidation. Significant reductions in [(3)H]epibatidine and [(125)I]alpha-bungarotoxin binding sites and in the protein levels of the alpha 3 and alpha 7 nAChR subunits were observed in the cells treated with A betas. Furthermore, A beta(25-35) decreased the level of ubiquinone-9 in PC12 cells, but did not change the amount of cholesterol, providing further evidence for lipid peroxidation. Interestingly, when PC12 cells were pretreated by antioxidant before the addition of A betas, the lipid peroxidation and the decreased ubiquinone resulted from A betas were prohibited. The decreases of nAChR binding sites and subunit proteins resulted from A betas were mostly prevented by the pretreatment with antioxidant. These findings suggest that lipid peroxidation stimulated by A betas might be a mechanism for the loss of nAChRs associated with the pathogenesis of AD.
Guan
Zhi-Zhong
ZZ
Department of Clinical Neuroscience, Occupational Therapy and Elderly Care Research, Division of Molecular Neuropharmacology, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden. zhizhong.guan@neurotec.ki.se
Yu
Wen-Feng
WF
Shan
Ke-Ren
KR
Nordman
Tomas
T
Olsson
Jerker
J
Nordberg
Agneta
A
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); C113041:amyloid beta-protein (35-25)