Elsevier

Neuroscience Letters

Volume 322, Issue 2, 5 April 2002, Pages 121-125
Neuroscience Letters

Inducible nitric oxide synthase and argininosuccinate synthetase: co-induction in brain tissue of patients with Alzheimer's dementia and following stimulation with β-amyloid 1–42 in vitro

https://doi.org/10.1016/S0304-3940(02)00095-2Get rights and content

Abstract

In Alzheimer's disease (AD), amyloid plaques within the brain are surrounded by activated glial cells (microglia and astrocytes). The mechanisms of glial activation and its effect on disease progression are not fully understood. Growing evidence suggests that beta-amyloid (Aβ) peptide, a major constituent of the amyloid plaque, is critically involved in the induction of an inflammatory response. The goal of this study was to examine the role of Aβ in the pathogenesis of local inflammation and neuronal cell death. We found increased mRNA levels of inducible nitric oxide synthase (iNOS) and the arginine regenerating enzyme argininosuccinate synthetase (ASS) within cortices of AD patients suggesting high output NO production. In vitro, synthetic Aβ1–42 and to a lesser extent Aβ1–40 induced iNOS and ASS transcription with consecutive NO overproduction in mixed rat neuronal-glial cultures. Furthermore, Aβ-stimulation lead to an increased release of inflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor-α. Again, Aβ1–42 had a much more pronounced effect as compared to Aβ1–40. Our data suggest that Aβ1–42 is a key mediator of glial activation and via the induction of inflammatory mediators may be a critical component of the neurodegenerative process in AD.

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Acknowledgements

We are indebted to Dr R. Sandbrink for providing us post mortem brain tissue. We also thank J. Pilz (Institute of Medical Biometry and Informatics, Department of Medical Informatic, University of Heidelberg), who has done the statistical analysis. This work was supported by the University of Heidelberg (“Forschungsschwerpunkt Geriatrie”), Germany.

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