title: Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype.
abstract: Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimer's disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages. We observed increased acetylation and phosphorylation of p53, coupled to reduced MDM2/p53 complex level and lower levels of SIRT1. Activation of p53 was associated with a number of targets (BAX, PARP1, caspase-3, p21, heat shock proteins, and PGC1α) that were modulated in both DS and DS/AD compared with age-matched controls. In particular, the most relevant changes (increased p-p53 and acetyl-p53 and reduced formation of MDM2/p53 complex) were found to be modified only in the presence of AD pathology in DS. In addition, a similar pattern of alterations in the p53 pathway was found in Ts65Dn mice. These results suggest that p53 may integrate different signals, which can result in a pro-apoptotic-phenotype contributing to AD neuropathology in people with DS.
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Tramutola
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Pupo
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Domenico
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy.|Universidad Autónoma de Chile, Instituto de Ciencias Biomédicas, Facultad de Salud, Providencia, Santiago, Chile.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Barone
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Arena
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Lanzillotta
authors.affiliation: Department of Neuropathology, University of Amsterdam (NL).
authors.forename: Diede
authors.initials: D
authors.lastname: Brokeaart
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Blarzino
authors.affiliation: Sanders-Brown Center of Aging, University of Kentucky, Lexington KY, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.affiliation: Sanders-Brown Center of Aging, University of Kentucky, Lexington KY, USA.|Department of Chemistry, University of Kentucky, Lexington KY, USA.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
mesh_terms: D000107:Acetylation; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D010641:Phenotype; D010766:Phosphorylation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: Apoptosis; Ts65Dn mouse model; caspase; p53; sirtuins; trisomy 21