Department of Pharmacology
Pharmacology and Neuroscience Graduate Program
Effects of TNFα-Converting Enzyme Inhibition on Amyloid β
Production and APP Processing In Vitro and In Vivo
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
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.