Department of Pharmacology
Pharmacology and Neuroscience Graduate Program
Journal Club

Effects of TNFα-Converting Enzyme ...
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Fall 2009-JC abstract flier


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Fall 2009-JC abstract flier

  1. 1. Department of Pharmacology Pharmacology and Neuroscience Graduate Program Journal Club Effects of TNFα-Converting Enzyme Inhibition on Amyloid β Production and APP Processing In Vitro and In Vivo Presented by: Nisha Rizvi Wednesday, December 2, 2009 – 3:00 p.m. Pharmacology Conference Room 3313 Inflammation is a major factor implicated in the pathogenesis of Alzheimer’s disease (AD). In many cell and animal models of AD, upregulation and/or increased release of inflammatory markers like tumor necrosis factor (TNF)-α, nitric oxide (NO), inducible nitric oxide synthase (iNOS) and interleukins (ILs) have been observed. There is clear evidence that these signaling molecules are toxic to neurons. TNF-α has been found to be over-expressed in AD and other neurodegenerative diseases. TNF receptor activation triggers various signaling cascades, including caspase-mediated programmed cell death. Single nucleotide polymorphisms (SNPs) in the TNF-α gene have been strongly linked to early onset AD and are believed to be associated with neuronal degeneration. It has been suggested that a vicious cycle of neuroinflammation and neuronal damage exists in the AD brain produced by an interplay between TNF-α secretion from activated microglia and β-amyloid (Aβ) production. TACE (TNF-α converting enzyme) is a proteolytic enzyme which cleaves membrane-bound proTNF-α to produce active soluble TNF-α. Therefore, its inhibitors demonstrate potential in alleviating TNFα-mediated inflammatory signaling in the AD brain. However, in addition to pro-TNF-α, TACE also utilizes amyloid precursor protein (APP) as its substrate and promotes its cleavage by α-secretase. Inhibition of TACE can thus lead to increased availability of APP for β-secretase (BACE) and stimulate the amyloidogenic pathway. The consequent increase in Aβ production would eliminate the possible therapeutic benefits of decreased TNF-α in AD. The present study however, demonstrates that even though TACE and BACE appear to share the same pool of substrate (APP), they do not necessarily compete for it. BACE processing of APP was found to be unaltered by TACE inhibition. In addition, TACE-mediated cleavage of APP was also unaffected by BACE inhibition. By using both in vitro and in vivo models, the authors demonstrate that BMS-561392 is a potent inhibitor of TACE and this inhibition does not lead to increased BACE processing of APP and no increase in Aβ40/42 production. They also report that BMS-561392 is more potent than TAPI-1 (a nonselective metalloprotease inhibitor) and is able to reduce APPα levels in both hippocampi and cerebrospinal fluid of Tg2576 mice, a transgenic model of Alzheimer’s disease, without increasing Aβ40/42. The authors suggest that though BMS-561392 is an unlikely agent for central TACE inhibition due to its inability to cross the blood-brain barrier, other CNS penetrating agents which selectively inhibit TACE may be beneficial in reducing TNF-α-mediated neuroinflammation without concomitant increase in Aβ40/42 production. Thus, TACE could serve as a possible target for treating AD. Refreshments served at 2:45 p.m.