The amyloid precursor protein (APP) of Alzheimer's disease is a transmembrane protein that is cleaved within its extracellular domain, liberating a soluble N-terminal fragment (sAPPα). Putative mediators of this process include three members of the ADAM (a disintegrin and metalloprotease) family, ADAM9, ADAM10 and ADAM17/TACE (tumour necrosis factor-α converting enzyme). Tumour necrosis factor-α protease inhibitor (TAPI-1), an inhibitor of ADAMs, reduced constitutive and muscarinic receptor-stimulated sAPPα release in HEK-293 cells stably expressing M3 muscarinic receptors. However, the former was less sensitive to TAPI-1 (IC50 = 8.09μM) than the latter (IC50 = 3.61μM), suggesting that these processes may be mediated by different metalloproteases. Constitutive sAPPα release was increased several-fold in cells transiently transfected with TACE, and this increase was proportional to TACE expression. In contrast, muscarinic-receptor-activated sAPPα release was not altered in TACE transfectants. TACE-dependent constitutive release of co-transfected APP695 was inhibited by TAPI-1 with an IC50 of 0.92μM, a value significantly lower than the IC50s for inhibition of either constitutive or receptor-regulated sAPPα shedding mediated by endogenous secretases. The results indicate that TACE is capable of catalysing constitutive α-secretory cleavage of APP, but it is likely that additional members of the ADAM family mediate endogenous constitutive and receptor-coupled release of sAPPα in HEK-293cells.
Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-α converting enzyme
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Barbara E. SLACK, Leona K. MA, Ching Ching SEAH; Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-α converting enzyme. Biochem J 1 August 2001; 357 (3): 787–794. doi: https://doi.org/10.1042/bj3570787
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