title: The purinergic receptor P2X7 triggers alpha-secretase-dependent processing of the amyloid precursor protein.
abstract: The amyloid precursor protein (APP) is cleaved by β- and γ-secretases to generate the β-amyloid (Aβ) peptides, which are present in large amounts in the amyloid plaques of Alzheimer disease (AD) patient brains. Non-amyloidogenic processing of APP by α-secretases leads to proteolytic cleavage within the Aβ peptide sequence and shedding of the soluble APP ectodomain (sAPPα), which has been reported to be endowed with neuroprotective properties. In this work, we have shown that activation of the purinergic receptor P2X7 (P2X7R) stimulates sAPPα release from mouse neuroblastoma cells expressing human APP, from human neuroblastoma cells and from mouse primary astrocytes or neural progenitor cells. sAPPα shedding is inhibited by P2X7R antagonists or knockdown of P2X7R with specific small interfering RNA (siRNA) and is not observed in neural cells from P2X7R-deficient mice. P2X7R-dependent APP-cleavage is independent of extracellular calcium and strongly inhibited by hydroxamate-based metalloprotease inhibitors, TAPI-2 and GM6001. However, knockdown of a disintegrin and metalloproteinase-9 (ADAM9), ADAM10 and ADAM17 by specific siRNA, known to have α-secretase activity, does not block the P2X7R-dependent non-amyloidogenic pathway. Using several specific pharmacological inhibitors, we demonstrate that the mitogen-activated protein kinase modules Erk1/2 and JNK are involved in P2X7R-dependent α-secretase activity. Our study suggests that P2X7R, which is expressed in hippocampal neurons and glial cells, is a potential therapeutic target in AD.
authors.affiliation: CRICM, INSERM UMR_S975, 75013 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Delarasse
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Auger
authors.forename: Pauline
authors.initials: P
authors.lastname: Gonnord
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Jean M
authors.initials: JM
authors.lastname: Kanellopoulos
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D004151:Dipeptides; D006877:Hydroxamic Acids; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D058486:Receptors, Purinergic P2X7; C099410:TAPI-2; D048052:Mitogen-Activated Protein Kinase 3; D048670:MAP Kinase Kinase 4; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins