Fibrillar beta-amyloid peptide Aβ1–40 activates microglial proliferation via stimulating TNF-α release and H2O2 derived from NADPH oxidase: a cell culture studyReportar como inadecuado




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Journal of Neuroinflammation

, 3:24

First Online: 07 September 2006Received: 16 March 2006Accepted: 07 September 2006

Abstract

BackgroundAlzheimer-s disease is characterized by the accumulation of neuritic plaques, containing activated microglia and β-amyloid peptides Aβ. Fibrillar Aβ can activate microglia, resulting in production of toxic and inflammatory mediators like hydrogen peroxide, nitric oxide, and cytokines. We have recently found that microglial proliferation is regulated by hydrogen peroxide derived from NADPH oxidase. Thus, in this study, we investigated whether Aβ can stimulate microglial proliferation and cytokine production via activation of NADPH oxidase to produce hydrogen peroxide.

MethodsPrimary mixed glial cultures were prepared from the cerebral cortices of 7-day-old Wistar rats. At confluency, microglial cells were isolated by tapping, replated, and treated either with or without Aβ. Hydrogen peroxide production by cells was measured with Amplex Red and peroxidase. Microglial proliferation was assessed under a microscope 0, 24 and 48 hours after plating. TNF-α and IL-1β levels in the culture medium were assessed by ELISA.

ResultsWe found that 1 μM fibrillar but not soluble Aβ1–40 peptide induced microglial proliferation and caused release of hydrogen peroxide, TNF-α and IL-1β from microglial cells. Proliferation was prevented by the NADPH oxidase inhibitor apocynin 10 μM, by the hydrogen peroxide-degrading enzyme catalase 60 U-ml, and by its mimetics EUK-8 and EUK-134 20 μM; as well as by an antibody against TNF-α and by a soluble TNF receptor inhibitor. Production of TNF-α and IL-1β, measured after 24 hours of Aβ treatment, was also prevented by apocynin, catalase and EUKs, but the early release measured after 1 hour of Aβ treatment of TNF-α was insensitive to apocynin or catalase.

ConclusionThese results indicate that Aβ1–40-induced microglial proliferation is mediated both by microglial release of TNF-α and production of hydrogen peroxide from NADPH oxidase. This suggests that TNF-α and NADPH oxidase, and its products, are potential targets to prevent Aβ-induced inflammatory neurodegeneration.

Electronic supplementary materialThe online version of this article doi:10.1186-1742-2094-3-24 contains supplementary material, which is available to authorized users.

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Autor: Aiste Jekabsone - Palwinder K Mander - Anna Tickler - Martyn Sharpe - Guy C Brown

Fuente: https://link.springer.com/



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