Effects of TNFα-Converting Enzyme Inhibition on Amyloid β Production and APP Processing In Vitro and In Vivo

Tumor necrosis factor-alpha(TNF alpha) is a proinflammatory cytokine that is elevated in Alzheimer's disease (AD) brains. Because TNF alpha is released from cell membranes by the TNF alpha-converting enzyme (TACE), inhibition of TACE has the potential to mitigate TNF alpha effects in AD brain. TACE also cleaves amyloid precursor protein (APP) and generates sAPP alpha, precluding the formation of potentially harmful amyloid beta (A beta) peptides by beta-site APP cleaving enzymes (BACE). Hence, the anti-inflammatory benefits of TACE inhibition might be offset by an increase in A beta. 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 sAPP alpha without a corresponding increase in A beta production. Conversely, a BACE inhibitor decreased sAPP beta and A beta peptides with no change in the secretion of sAPP alpha. 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 sAPP alpha levels were observed, steady-state A beta levels were not significantly changed. Accordingly, it is possible that TACE inhibitors could reduce TNF alpha levels without increasing A beta levels within the AD brain.