title: Synergistic amplification of beta-amyloid- and interferon-gamma-induced microglial neurotoxic response by the senile plaque component chromogranin A.
abstract: 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-alpha (TNFalpha), and hydrogen peroxide. Central to the activation of microglia is the membrane receptor CD40, which is the target of costimulators such as interferon-gamma (IFNgamma). 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 TNFalpha, 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 beta-amyloid (betaA) under identical conditions and found that CGA induces 5-7 times greater NO and TNFalpha secretion. Coapplication of CGA with betaA or with IFNgamma resulted in a synergistic effect on NO and TNFalpha secretion. CD40 expression was induced by CGA and was further increased when betaA or IFNgamma 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 IFNgamma and betaA. 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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Gilad
authors.initials: G
authors.lastname: Twig
authors.forename: Solomon A
authors.initials: SA
authors.lastname: Graf
authors.forename: Mark A
authors.initials: MA
authors.lastname: Messerli
authors.forename: Peter J S
authors.initials: PJ
authors.lastname: Smith
authors.forename: Seung H
authors.initials: SH
authors.lastname: Yoo
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019013:CD40 Antigens / Q000378:metabolism; D002417:Cattle; D019439:Chromaffin Cells / Q000166:cytology; D053379:Chromogranin A; D002864:Chromogranins / Q000494:pharmacology*; D004357:Drug Synergism; D007371:Interferon-gamma / Q000494:pharmacology*; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D058225:Plaque, Amyloid / Q000378:metabolism; D051381:Rats; D016897:Respiratory Burst / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D053379:Chromogranin A; D002864:Chromogranins; D020032:Tyrphostins; C506153:chromogranin A, rat; D007371:Interferon-gamma; C060641:tyrphostin A23