?-Secretase-derived fragment of cellular prion, N1, protects against monomeric and oligomeric amyloid ? (A?)-associated cell death.

ABSTRACT: In physiological conditions, both ?-amyloid precursor protein (?APP) and cellular prion (PrP(c)) undergo similar disintegrin-mediated ?-secretase cleavage yielding N-terminal secreted products referred to as soluble amyloid precursor protein-? (sAPP?) 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 ? (A?)-mediated toxicity. We first show that both recombinant sAPP? 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 ?APP overexpression in human cells. We designed a CHO cell line overexpressing the London mutated ?APP (APP(LDN)) that yields A? 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 A?-associated toxicity and that its production could be seen as a cellular protective mechanism aimed at compensating for an sAPP? deficit taking place at the early asymptomatic phase of Alzheimer disease.

SUBMITTER: Guillot-Sestier MV 

PROVIDER: S-EPMC3281657 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature