Constitutive α- and β-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines
| Autor: | Peter J. Dempsey, Alessio Colombo, Huanhuan Wang, Howard C. Crawford, Richard M. Page, Stefan F. Lichtenthaler, Peer-Hendrik Kuhn, Elisabeth Kremmer |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
ADAM10
genetics [Amyloid Precursor Protein Secretases] genetics [ADAM Proteins] antagonists & inhibitors [Amyloid Precursor Protein Secretases] APP protein human drug effects [Cerebral Cortex] antagonists & inhibitors [Membrane Proteins] ADAM10 Protein Amyloid beta-Protein Precursor enzymology [Cerebral Cortex] metabolism [Amyloid beta-Protein Precursor] Adam10 protein mouse Amyloid precursor protein Aspartic Acid Endopeptidases Cells Cultured Cerebral Cortex Mice Knockout Neurons enzymology [Neurons] biology Beta-secretase P3 peptide antagonists & inhibitors [Aspartic Acid Endopeptidases] metabolism [Aspartic Acid Endopeptidases] Alzheimer's disease Cell biology genetics [Membrane Proteins] Neurology Biochemistry Alpha secretase Gene Knockdown Techniques pharmacology [Protease Inhibitors] antagonists & inhibitors [ADAM Proteins] Proteases Bace1 protein mouse ADAM10 protein human Cleavage (embryo) Article lcsh:RC321-571 ddc:570 BACE1 protein human Cell Line Tumor mental disorders drug effects [Neurons] Animals Humans Protease Inhibitors lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry HEK 293 cells Membrane Proteins metabolism [Amyloid Precursor Protein Secretases] ADAM Proteins HEK293 Cells genetics [Aspartic Acid Endopeptidases] metabolism [ADAM Proteins] biology.protein Alpha-secretase Amyloid Precursor Protein Secretases Amyloid precursor protein secretase metabolism [Membrane Proteins] |
| Zdroj: | Neurobiology of Disease, Vol 49, Iss, Pp 137-147 (2013) Neurobiology of disease 49, 137-147 (2013). doi:10.1016/j.nbd.2012.08.011 |
| DOI: | 10.1016/j.nbd.2012.08.011 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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