%0 Journal Article %J J Alzheimers Dis %D 2018 %T Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models. %A Lanzillotta, Chiara %A Tramutola, Antonella %A Meier, Shelby %A Schmitt, Frederick %A Barone, Eugenio %A Perluigi, Marzia %A Di Domenico, Fabio %A Abisambra, Jose F %X

Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer's disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involved in the formation of amyloid plaques and tau tangles. Further, DS and AD are characterized by the aberrant accumulation of unfolded/misfolded proteins resulting from over-burdened protein quality control systems. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR). Long-term activation of the UPR mediates neuronal dysfunction in AD. We hypothesized that the UPR is impacted in a mouse model of DS. To test this, we performed gene and protein expression analysis of ER stress markers in the Ts65Dn mouse model of DS at 3, 9, and 18 months. We identified activation of the PERK pathway in Ts65Dn DS mice at 3 months of age compared to euploid controls. We also determined that the early and overt UPR activation decreased with age, the UPR signal was significantly reduced by 18 months. Our data suggest that UPR activation in DS mouse models occurs early before consistent brain neurodegeneration and might be an essential contributor to dys-proteostasis.

%B J Alzheimers Dis %V 62 %P 347-359 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29439332?dopt=Abstract %R 10.3233/JAD-170617 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype. %A Tramutola, Antonella %A Pupo, Gilda %A Di Domenico, Fabio %A Barone, Eugenio %A Arena, Andrea %A Lanzillotta, Chiara %A Broekaart, Diede %A Blarzino, Carla %A Head, Elizabeth %A Butterfield, D Allan %A Perluigi, Marzia %K Acetylation %K Alzheimer Disease %K Animals %K Apoptosis %K Blotting, Western %K Disease Models, Animal %K Down Syndrome %K Female %K Frontal Lobe %K Humans %K Immunoprecipitation %K Male %K Mice, Inbred C3H %K Mice, Inbred C57BL %K Mice, Transgenic %K Middle Aged %K Phenotype %K Phosphorylation %K Tumor Suppressor Protein p53 %K Young Adult %X

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.

%B J Alzheimers Dis %V 52 %P 359-71 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967221?dopt=Abstract %R 10.3233/JAD-151105