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This Article Full Text Full Text (PDF) All Versions of this Article: 288/1/C169    most recent 00308.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Twig, G. Articles by Shirihai, O. S. Search for Related Content PubMed PubMed Citation Articles by Twig, G. Articles by Shirihai, O. S.

RECEPTORS AND SIGNAL TRANSDUCTION

Synergistic amplification of -amyloid- and interferon--induced microglial neurotoxic response by the senile plaque component chromogranin A

¹Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston; ²BioCurrents Research Center, Program in Molecular Physiology, Marine Biological Laboratory, Woods Hole, Massachusetts; ³Department of Physiology, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; and ⁴National Creative Research Initiative Center for Secretory Granule Research and Department of Biochemistry, Inha University College of Medicine, Incheon, Korea

Submitted 30 June 2004 ; accepted in final form 23 August 2004

Activation of the microglial neurotoxic response by components of the senile plaque plays a critical role in the pathophysiology of Alzheimer's disease (AD). Microglia induce neurodegeneration primarily by secreting nitric oxide (NO), tumor necrosis factor- (TNF), and hydrogen peroxide. Central to the activation of microglia is the membrane receptor CD40, which is the target of costimulators such as interferon- (IFN). Chromogranin A (CGA) is a recently identified endogenous component of the neurodegenerative plaques of AD and Parkinson's disease. CGA stimulates microglial secretion of NO and TNF, resulting in both neuronal and microglial apoptosis. Using electrochemical recording from primary rat microglial cells in culture, we have shown in the present study that CGA alone induces a fast-initiating oxidative burst in microglia. We compared the potency of CGA with that of -amyloid (A) under identical conditions and found that CGA induces 5–7 times greater NO and TNF secretion. Coapplication of CGA with A or with IFN resulted in a synergistic effect on NO and TNF secretion. CD40 expression was induced by CGA and was further increased when A or IFN was added in combination. Tyrphostin A1 (TyrA1), which inhibits the CD40 cascade, exerted a dose-dependent inhibition of the CGA effect alone and in combination with IFN and A. Furthermore, CGA-induced mitochondrial depolarization, which precedes microglial apoptosis, was fully blocked in the presence of TyrA1. Our results demonstrate the involvement of CGA with other components of the senile plaque and raise the possibility that a narrowly acting agent such as TyrA1 attenuates plaque formation.

Alzheimer's disease; oxidative burst; apoptosis; nitric oxide; tyrphostin A1