The University of Southampton
University of Southampton Institutional Repository

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

Synergistic amplification of beta-amyloid-and interferon-?-induced microglial neurotoxic response by the senile plaque component chromogranin A
Synergistic amplification of beta-amyloid-and interferon-?-induced microglial neurotoxic response by the senile plaque component chromogranin A
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 {beta}-amyloid ({beta}A) under identical conditions and found that CGA induces 5–7 times greater NO and TNF? secretion. Coapplication of CGA with {beta}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 {beta}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 {beta}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
0363-6143
C169-C175
Twig, Gilad
d9f75e6e-eac7-4a82-923f-08e1b318e70c
Graf, Solomon A.
cd6bb55a-d830-4485-816e-859051f2f460
Messerli, Mark A.
94a8bd34-95d7-4a52-b4d8-1ccded0e8fe7
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Yoo, Seung H.
2c126d7d-cfc8-4aea-a2f3-46a731c97ac4
Shirihai, Orian S.
3fcd01e8-1cb6-498d-a2c5-8e799ef00b72
Twig, Gilad
d9f75e6e-eac7-4a82-923f-08e1b318e70c
Graf, Solomon A.
cd6bb55a-d830-4485-816e-859051f2f460
Messerli, Mark A.
94a8bd34-95d7-4a52-b4d8-1ccded0e8fe7
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Yoo, Seung H.
2c126d7d-cfc8-4aea-a2f3-46a731c97ac4
Shirihai, Orian S.
3fcd01e8-1cb6-498d-a2c5-8e799ef00b72

Twig, Gilad, Graf, Solomon A., Messerli, Mark A., Smith, Peter J.S., Yoo, Seung H. and Shirihai, Orian S. (2005) Synergistic amplification of beta-amyloid-and interferon-?-induced microglial neurotoxic response by the senile plaque component chromogranin A. American Journal of Physiology: Cell Physiology, 288 (1), C169-C175. (doi:10.1152/ajpcell.00308.2004).

Record type: Article

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-? (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 {beta}-amyloid ({beta}A) under identical conditions and found that CGA induces 5–7 times greater NO and TNF? secretion. Coapplication of CGA with {beta}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 {beta}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 {beta}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

Text
Am_J_Physiol_Cell_Physiol-2005-Twig-C169-75.pdf - Version of Record
Restricted to Repository staff only
Request a copy

More information

Published date: January 2005
Organisations: University of Southampton

Identifiers

Local EPrints ID: 190599
URI: http://eprints.soton.ac.uk/id/eprint/190599
ISSN: 0363-6143
PURE UUID: b2636339-0247-48fa-b439-a8577c8947b9
ORCID for Peter J.S. Smith: ORCID iD orcid.org/0000-0003-4400-6853

Catalogue record

Date deposited: 20 Jun 2011 07:46
Last modified: 03 Dec 2019 01:40

Export record

Altmetrics

Contributors

Author: Gilad Twig
Author: Solomon A. Graf
Author: Mark A. Messerli
Author: Seung H. Yoo
Author: Orian S. Shirihai

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×