Proprotein convertase activity contributes to the processing of the Alzheimer's beta-amyloid precursor protein in human cells: evidence for a role of the prohormone convertase PC7 in the constitutive alpha-secretase pathway.
The physiological maturation of the beta-amyloid precursor protein (betaAPP) leads to the secretion of a fragment termed APPalpha, after cleavage by a proteolytic enzyme called-secretase. In Alzheimer's disease, betaAPP undergoes exacerbated proteolytic attacks by beta- and gamma-secretases, which liberate a readily aggregatable 40-42-amino acid peptide called AP. We show here that overexpression of the prohormone convertase PC7 triggers increased secretion of APPalpha and lowers both Abeta40 and Abeta42 recoveries. Overexpression of alpha1-antitrypsin Portland (alpha1-PDX), which blocks mammalian precursor convertases of the constitutive secretory pathway, reverses the PC7-induced APPalpha increase as well as the decrease of Abeta40/42 in HEK293 cells. It is interesting that alpha1-PDX also lowers the level of APPalpha endogenously produced by mock-transfected HEK293 cells. Finally, a Jurkat clone stably expressing alpha1-PDX produces noticeably lower amounts of APPalpha. Therefore, this serpin affects endogenous a-secretase activity/pathway in distinct cell types. By contrast, alpha1-PDX does not alter the processing of presenilin 1 or its mutated congeners linked to some familial forms of Alzheimer's disease. Altogether, we demonstrate that a prohormone convertase participates in the alpha-secretase pathway of betaAPP maturation in human cells and concomitantly contributes to slowing the pathogenic route leading to the formation of Abeta. Our data strongly suggest that PC7 could fulfill such a role.
Lopez-Perez
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E
IPMC du CNRS, UPR 411, Sophia Antipolis, Valbonne, France.
Seidah
N G
NG
Checler
F
F
D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045683:Furin; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1; D051381:Rats; D013381:Subtilisins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D000515:alpha 1-Antitrypsin; C113421:alpha 1-antitrypsin Portland; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D013381:Subtilisins; D045683:Furin; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human