title: α-Secretase-derived fragment of cellular prion, N1, protects against monomeric and oligomeric amyloid β (Aβ)-associated cell death.
abstract: In physiological conditions, both β-amyloid precursor protein (βAPP) and cellular prion (PrP(c)) undergo similar disintegrin-mediated α-secretase cleavage yielding N-terminal secreted products referred to as soluble amyloid precursor protein-α (sAPPα) and N1, respectively. We recently demonstrated that N1 displays neuroprotective properties by reducing p53-dependent cell death both in vitro and in vivo. In this study, we examined the potential of N1 as a neuroprotector against amyloid β (Aβ)-mediated toxicity. We first show that both recombinant sAPPα and N1, but not its inactive parent fragment N2, reduce staurosporine-stimulated caspase-3 activation and TUNEL-positive cell death by lowering p53 promoter transactivation and activity in human cells. We demonstrate that N1 also lowers toxicity, cell death, and p53 pathway exacerbation triggered by Swedish mutated βAPP overexpression in human cells. We designed a CHO cell line overexpressing the London mutated βAPP (APP(LDN)) that yields Aβ oligomers. N1 protected primary cultured neurons against toxicity and cell death triggered by oligomer-enriched APP(LDN)-derived conditioned medium. Finally, we establish that N1 also protects neurons against oligomers extracted from Alzheimer disease-affected brain tissues. Overall, our data indicate that a cellular prion catabolite could interfere with Aβ-associated toxicity and that its production could be seen as a cellular protective mechanism aimed at compensating for an sAPPα deficit taking place at the early asymptomatic phase of Alzheimer disease.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097 CNRS/Université de Nice-Sophia-Antipolis (UNSA), 660 route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France.
authors.forename: Marie-Victoire
authors.initials: MV
authors.lastname: Guillot-Sestier
authors.forename: Claire
authors.initials: C
authors.lastname: Sunyach
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
authors.forename: Maria-Paz
authors.initials: MP
authors.lastname: Marzolo
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bauer
authors.forename: Aurélie
authors.initials: A
authors.lastname: Thevenet
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D019311:Staurosporine / Q000494:pharmacology
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D010455:Peptides; D018621:PrPC Proteins; D053829:Amyloid Precursor Protein Secretases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D019311:Staurosporine