Effect of tumor necrosis factor-alpha converting enzyme (TACE) and metalloprotease inhibitor on amyloid precursor protein metabolism in human neurons.
Tumor necrosis factor-alpha (TNF-alpha) is implicated in inflammatory processes and much effort is being directed at inhibiting the release of TNF-alpha for treatment of inflammatory conditions. In this context, the drug CP-661,631 has been developed to inhibit the TNF-alpha converting enzyme (TACE). However, TACE is also implicated in amyloid precursor protein secretion. Amyloid precursor protein (APP) undergoes constitutive and regulated secretion by alpha-secretase endoproteolytic cleavage within the amyloid beta peptide (Abeta) domain. Alternative cleavage at the N- and C-terminus of the Abeta domain by beta- and gamma-secretases results in the production of Abeta. In many cellular and in vivo animal models, increased secretion of APP results in a concomitant decrease in the production of Abeta suggesting that the two pathways are intricately linked. However, in human primary neuron cultures, increased APP secretion is not associated with a decrease in total Abeta production. To determine if the use of CP-661,631 may enhance amyloidogenic processing in human brain, we have assessed the effect of CP-661,631 on APP metabolism in primary cultures of human neurons. Our results show that CP-661,631 effectively prevents regulated APP secretion but does not increase total Abeta levels in human primary neuron cultures.
Blacker
Megan
M
The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
Noe
Mark C
MC
Carty
Thomas J
TJ
Goodyer
Cynthia G
CG
LeBlanc
Andréa C
AC
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology* / Q000633:toxicity; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology* / Q000633:toxicity; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology
C470304:1-(4-(4-fluoro-2-methylbenzyloxy)benzenesulfonyl)-3-hydroxy-3-methylpiperidine-2-carboxylic acid hydroxyamide; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D010880:Piperidines; D013450:Sulfones; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D013755:Tetradecanoylphorbol Acetate