Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype
| Autor: | Chiara Lanzillotta, Marzia Perluigi, Elizabeth Head, Gilda Pupo, D. Allan Butterfield, Fabio Di Domenico, Carla Blarzino, Eugenio Barone, Andrea Arena, Diede W. M. Broekaart, Antonella Tramutola |
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| Přispěvatelé: | Cassano, Tommaso |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male p53 Aging Apoptosis Neurodegenerative apoptosis ts65dn mouse model caspase sirtuins trisomy 21 Inbred C57BL Alzheimer's Disease Transgenic Mice 2.1 Biological and endogenous factors Senile plaques Phosphorylation Aetiology Mice Inbred C3H Blotting General Neuroscience Acetylation General Medicine Middle Aged Inbred C3H Frontal Lobe Psychiatry and Mental health Clinical Psychology Phenotype Neurological Female Cognitive Sciences Alzheimer's disease Western medicine.medical_specialty Down syndrome Upstream and downstream (transduction) Intellectual and Developmental Disabilities (IDD) Blotting Western Clinical Sciences Mice Transgenic Neuropathology Biology Article Ts65Dn mouse model 03 medical and health sciences Young Adult Alzheimer Disease Internal medicine Heat shock protein medicine Genetics Acquired Cognitive Impairment Animals Humans Immunoprecipitation Neurology & Neurosurgery Animal Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) medicine.disease Brain Disorders Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology Immunology Disease Models Dementia Geriatrics and Gerontology Down Syndrome Tumor Suppressor Protein p53 Trisomy Chromosome 21 |
| Zdroj: | Journal of Alzheimer's disease : JAD, vol 52, iss 1 |
| Popis: | 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, 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-mediated ubiquitination and lower levels of SIRT1. Activation of p53 was associated with a number of down-stream targets (bax, PARP1, caspase-3, 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, 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 were 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. |
| Databáze: | OpenAIRE |
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