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Colombo, A.* ; Wang, H.* ; Kuhn, P.H.* ; Page, R.* ; Kremmer, E. ; Dempsey, P.J.* ; Crawford, H.C.* ; Lichtenthaler, S.F.*

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

Neurobiol. Dis. 49, 137-147 (2012)

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Open Access Green as soon as Postprint is submitted to ZB.

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Proteolytic cleavage of the amyloid precursor protein (APP) by the two proteases α- and β-secretases controls the generation of the amyloid β peptide (Aβ), a key player in Alzheimer's disease pathogenesis. The α-secretase ADAM10 and the β-secretase BACE1 have opposite effects on Aβ 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 α- and β-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 α-secretase cleavage of APP is largely uncoupled from β-secretase cleavage and Aβ 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 α- and β-secretase cleavages depends on the cellular model and suggests that a reduction of ADAM10 activity is unlikely to increase the AD risk through increased β-secretase cleavage.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Alzheimer's disease; Alpha-secretase; Beta-secretase; Amyloid precursor protein

ISSN (print) / ISBN 0969-9961

e-ISSN 1095-953X

Journal Neurobiology of Disease

Quellenangaben Volume: 49, Pages: 137-147

Publisher Elsevier

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Molecular Immunology (IMI)