Effects of TNFα-Converting Enzyme Inhibition on Amyloid β Production and APP ProcessingIn VitroandIn Vivo

Nov 14, 2008The Journal of neuroscience : the official journal of the Society for Neuroscience

How Blocking TNFalpha-Processing Enzyme May Change Amyloid Beta Production and Protein Processing in Lab and Living Systems

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Abstract

Inhibition of TACE with the compound BMS-561392 reduced sAPPalpha levels in the brain without significantly changing Abeta levels.

Tumor necrosis factor-alpha (TNFalpha) is elevated in Alzheimer's disease brains and is linked to inflammation.
TACE plays a role in processing amyloid precursor protein (APP) and generating sAPPalpha, which may help prevent harmful amyloid beta (Abeta) production.
BMS-561392 reduced sAPPalpha secretion in cell models without leading to an increase in Abeta production.
A BACE inhibitor decreased sAPPbeta and Abeta levels but did not affect sAPPalpha secretion, indicating no competition for the APP substrate under normal conditions.
Enhanced TACE activity may lead to competition for APP in specific conditions, but this was not observed in normal circumstances.
In vivo infusion of BMS-561392 into mouse brains showed decreased sAPPalpha levels while steady-state Abeta levels remained unchanged.

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Tumor necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine that is elevated in Alzheimer's disease (AD) brains. Because TNFalpha is released from cell membranes by the TNFalpha-converting enzyme (TACE), inhibition of TACE has the potential to mitigate TNFalpha effects in AD brain. TACE also cleaves amyloid precursor protein (APP) and generates sAPPalpha, precluding the formation of potentially harmful amyloid beta (Abeta) peptides by beta-site APP cleaving enzymes (BACE). Hence, the anti-inflammatory benefits of TACE inhibition might be offset by an increase in Abeta. We have examined the effects of the highly selective TACE inhibitor, BMS-561392, on APP processing in vitro and in vivo. In Chinese hamster ovary cells expressing APP, BMS-561392 significantly reduced secretion of sAPPalpha without a corresponding increase in Abeta production. Conversely, a BACE inhibitor decreased sAPPbeta and Abeta peptides with no change in the secretion of sAPPalpha. These data indicate an absence of TACE and BACE competition for the APP substrate. Despite this, we observed competition for APP when TACE activity was enhanced via phorbol ester treatment or if APP was modified such that it was retained within the trans-Golgi network (TGN). These results suggest that BACE and TACE share a common TGN localization, but under normal conditions do not compete for APP. To confirm this finding in vivo, BMS-561392 was infused into the brains of Tg2576 and wild-type mice. Although decreased brain sAPPalpha levels were observed, steady-state Abeta levels were not significantly changed. Accordingly, it is possible that TACE inhibitors could reduce TNFalpha levels without increasing Abeta levels within the AD brain.

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Effects of TNFα-Converting Enzyme Inhibition on Amyloid β Production and APP ProcessingIn VitroandIn Vivo

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