Constitutive α- and β-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines

Proteolytic cleavage of the amyloid precursor protein (APP) by the two proteases alpha- and beta-secretases controls the generation of the amyloid beta peptide (A beta), a key player in Alzheimer's disease pathogenesis. The alpha-secretase ADAM10 and the beta-secretase BACE1 have opposite effects on A beta generation and are assumed to compete for APP as a substrate, such that their cleavages are inversely coupled. This concept was mainly demonstrated in studies using activation or overexpression of alpha- and beta-secretases. Here, we report that this inverse coupling is not seen to the same extent upon inhibition of the endogenous proteases. Genetic and pharmacological inhibition of ADAM10 and BACE1 revealed that the endogenous, constitutive alpha-secretase cleavage of APP is largely uncoupled from beta-secretase cleavage and A beta generation in neuroglioma H4 cells and in neuronally differentiated SH-SY5Y cells. In contrast, inverse coupling was observed in primary cortical neurons. However, this coupling was not bidirectional. Inhibition of BACE1 increased ADAM10 cleavage of APP, but a reduction of ADAM10 activity did not increase the BACE1 cleavage of APP in the neurons. Our analysis shows that the inverse coupling of the endogenous alpha- and beta-secretase cleavages depends on the cellular model and suggests that a reduction of ADAM10 activity is unlikely to increase the AD risk through increased beta-secretase cleavage. (C) 2012 Elsevier Inc. All rights reserved.