Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid beta-peptide-induced cholinergic dysfunction.
Amyloid beta (Abeta) is a critical factor involved in the pathogenesis of Alzheimer's disease (AD). We have previously demonstrated that continuous intracerebroventricular infusion of Abeta1-40 induced a time-dependent expression of the inducible nitric oxide (NO) synthase (iNOS) and an overproduction of NO in the rat hippocampus. The pathophysiological significance of the overproduction of NO on brain function was manifested by an impairment of nicotine-evoked acetylcholine(ACh) release and memory deficits.(4) Molecular mechanisms by which NO participates in the Abeta-induced brain dysfunction, however, remain to be determined. Here we show that chronic Abeta1-40 infusion caused a robust peroxynitrite formation and subsequent tyrosine nitration of proteins in the hippocampus. Immunoprecipitation and Western blot analyses further revealed that synaptophysin, a synaptic protein, was a main target of tyrosine nitration. Chronic infusion of Abeta1-40 resulted in an impairment of nicotine-evoked ACh release as analyzed by microdialysis. Daily treatment with the iNOS inhibitor aminoguanidine (AG) or the peroxynitrite scavenger uric acid (UA) prevented the tyrosine nitration of synaptophysin as well as the impairment of nicotine-evoked ACh release induced by Abeta. Our findings suggest that the tyrosine nitration of synaptophysin is related to Abeta-induced impairment of ACh release.
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan. tnabeshi@med.nagoya-u.ac.jp
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D000109:Acetylcholine / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007263:Infusions, Parenteral; D008297:Male; D017551:Microdialysis / Q000379:methods; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D016708:Synaptophysin; C078592:amyloid beta-protein (1-40); D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D000109:Acetylcholine