title: Familial Alzheimer's Disease Lymphocytes Respond Differently Than Sporadic Cells to Oxidative Stress: Upregulated p53-p21 Signaling Linked with Presenilin 1 Mutants.
abstract: Familial (FAD) and sporadic (SAD) Alzheimer's disease do not share all pathomechanisms, but knowledge on their molecular differences is limited. We previously reported that cell cycle control distinguishes lymphocytes from SAD and FAD patients. Significant differences were found in p21 levels of SAD compared to FAD lymphocytes. Since p21 can also regulate apoptosis, the aim of this study was to compare the response of FAD and SAD lymphocytes to oxidative stress like 2-deoxy-D-ribose (2dRib) treatment and to investigate the role of p21 levels in this response. We report that FAD cells bearing seven different PS1 mutations are more resistant to 2dRib-induced cell death than control or SAD cells: FAD cells showed a lower apoptosis rate and a lower depolarization of the mitochondrial membrane. Despite that basal p21 cellular content was lower in FAD than in SAD cells, in response to 2dRib, p21 mRNA and protein levels significantly increased in FAD cells. Moreover, we found a higher cytosolic accumulation of p21 in FAD cells. The transcriptional activation of p21 was shown to be dependent on p53, as it can be blocked by PFT-α, and correlated with the increased phosphorylation of p53 at Serine 15. Our results suggest that in FAD lymphocytes, the p53-mediated increase in p21 transcription, together with a shift in the nucleocytoplasmic localization of p21, confers a survival advantage against 2dRib-induced apoptosis. This compensatory mechanism is absent in SAD cells. Thus, therapeutic and diagnostic designs should take into account possible differential apoptotic responses in SAD versus FAD cells.
authors.affiliation: Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Pasteur 3, 02-093, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wojsiat
authors.affiliation: Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Pasteur 3, 02-093, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Laskowska-Kaszub
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.|CIBER de Enfermedades Raras (CIBERER), 28040, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Alquézar
authors.affiliation: Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Pasteur 3, 02-093, Warsaw, Poland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Białopiotrowicz
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.|CIBER de Enfermedades Raras (CIBERER), 28040, Madrid, Spain.
authors.forename: Noemi
authors.initials: N
authors.lastname: Esteras
authors.affiliation: Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Pasteur 3, 02-093, Warsaw, Poland.
authors.forename: Mykola
authors.initials: M
authors.lastname: Zdioruk
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.|CIBER de Enfermedades Raras (CIBERER), 28040, Madrid, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Martin-Requero
authors.affiliation: Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Pasteur 3, 02-093, Warsaw, Poland. u.wojda@nencki.gov.pl.
authors.forename: Urszula
authors.initials: U
authors.lastname: Wojda
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053764:Presenilin-1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: 2-deoxy-D-ribose; Apoptosis; Familial Alzheimer’s disease; Lymphocytes; Mitochondrial membrane potential; Oxidative stress; Presenilin; Sporadic Alzheimer’s disease; p21; p53