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Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid β-peptide-induced cholinergic dysfunction

Molecular Psychiatry volume 8, pages 407–412 (2003)Cite this article

Abstract

Amyloid β (Aβ) is a critical factor involved in the pathogenesis of Alzheimer's disease (AD). We have previously demonstrated that continuous intracerebroventricular infusion of Aβ1–40 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 Aβ-induced brain dysfunction, however, remain to be determined. Here we show that chronic Aβ1–40 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 Aβ1–40 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 Aβ. Our findings suggest that the tyrosine nitration of synaptophysin is related to Aβ-induced impairment of ACh release.

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Acknowledgements

This study was supported in part by Grants-in-Aid for Science Research (No. 14370031) and Special Coordination Funds for Promoting Science and Technology, Target-Oriented Brain Science Research Program, from the Ministry of Education, Culture, Sports, Science and Technology of Japan and an SRF Grant for Biomedical Research.

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Author notes

  1. Contributed equally to this work.

  2. Present address of: Laboratory of Experimental Therapeutics, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-0934, Japan.

Authors and Affiliations

  1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan

    M H Tran, K Yamada, A Nakajima, M Mizuno, J He, H Kamei & T Nabeshima

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  1. M H Tran
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  2. K Yamada
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  4. M Mizuno
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  7. T Nabeshima
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Correspondence to T Nabeshima.

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Tran, M., Yamada, K., Nakajima, A. et al. Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid β-peptide-induced cholinergic dysfunction. Mol Psychiatry 8, 407–412 (2003). https://doi.org/10.1038/sj.mp.4001240

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