Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models
Authors: Lanzillotta, Chiara | Tramutola, Antonella | Meier, Shelby | Schmitt, Frederick | Barone, Eugenio | Perluigi, Marzia | Di Domenico, Fabio | Abisambra, Jose F.
Article Type: Research Article
Abstract: 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. Show more
Keywords: Down syndrome, eif2 alpha, PERK, Ts65Dn, unfolded protein response
DOI: 10.3233/JAD-170617
Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 347-359, 2018
Oxidative and Nitrosative Modifications of Biliverdin Reductase-A in the Brain of Subjects with Alzheimer's Disease and Amnestic Mild Cognitive Impairment
Authors: Barone, Eugenio | Di Domenico, Fabio | Cenini, Giovanna | Sultana, Rukhsana | Coccia, Raffaella | Preziosi, Paolo | Perluigi, Marzia | Mancuso, Cesare | Butterfield, D. Allan
Article Type: Research Article
Abstract: Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme and plays pivotal role in the antioxidant defense against free radicals as well as in cell homeostasis. Together with heme oxygenase, BVR-A forms a powerful system involved in the cell stress response during neurodegenerative disorders including Alzheimer's disease (AD), whereas due to the serine/threonine/tyrosine kinase activity the enzyme regulates glucose metabolism and cell proliferation. In this paper, we report results that demonstrate BVR-A undergoes post-translational oxidative and nitrosative modifications in the hippocampus, but not cerebellum, of subjects with AD and amnestic mild cognitive impairment (MCI). A significant increase of nitrated BVR-A was demonstrated …only in AD and MCI hippocampi, whereas no significant modifications were found in cerebellar tissue. In addition, a significant reduction in protein carbonyl-derivatives of BVR-A was found in both AD and MCI hippocampi (15% and 18%, respectively). Biliverdin reductase-bound 4-hydroxynonenals were not modified in hippocampi and cerebella from AD and MCI subjects. These results supported the hypothesis of a prevalence of nitrosative stress-induced modifications on BVR-A structure, and this evidence was confirmed by a significant upregulation of inducible nitric oxide synthase in hippocampal tissue of subjects with AD and MCI that was not present in cerebellum. In conclusion, nitrosative stress-induced modifications on hippocampal BVR-A are an early event in the pathogenesis of AD since they appear also in MCI subjects and could contribute to the antioxidant and metabolic derangement characteristic of these neurodegenerative disorders. Show more
Keywords: Alzheimer's disease, biliverdin reductase, heme oxygenase, mild cognitive impairment, neurodegenerative disorders, oxidative stress
DOI: 10.3233/JAD-2011-110092
Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 623-633, 2011
HO-1/BVR-A System Analysis in Plasma from Probable Alzheimer's Disease and Mild Cognitive Impairment Subjects: A Potential Biochemical Marker for the Prediction of the Disease
Authors: Di Domenico, Fabio | Barone, Eugenio | Mancuso, Cesare | Perluigi, Marzia | Cocciolo, Annalisa | Mecocci, Patrizia | Butterfield, D. Allan | Coccia, Raffaella
Article Type: Research Article
Abstract: Several studies showed increased oxidative and nitrosative stress in plasma from patients with Alzheimer's disease (AD), however, little and controversial knowledge has emerged about the antioxidant functionality of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system in blood. The current study reports increased levels of both HO-1 and BVR-A in plasma from probable AD patients, as a result of the increased oxidative environment. However, the increase of oxidative stress in plasma result also in the increase of BVR-A 3-nitrotyrosine levels and the decrease of BVR-A phosphotyrosine levels and reductase activity, suggesting that nitrosative stress play the prominent oxidative role in plasma during …AD. Our data on HO-1/BVR-A status in plasma closely correlate with recent reports in hippocampus of subjects with AD and arguably its early form, mild cognitive impairment. Moreover, we show that alterations on HO-1/BVR-A system are tightly connected with cognitive decline indexed by Mini-Mental Status Exam scores. We hypothesize that the HO-1/BVR-A system status in plasma might reflect the ongoing situation in the brain, offering an important biochemical tool for the potential prediction of AD at the earliest stages of the disease. Show more
Keywords: Alzheimer disease's, bilirubin, biliverdin reductase-A, heme oxygenase-1, oxidative/nitrosative stress
DOI: 10.3233/JAD-2012-121045
Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 277-289, 2012
Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype
Authors: Tramutola, Antonella | Pupo, Gilda | Di Domenico, Fabio | Barone, Eugenio | Arena, Andrea | Lanzillotta, Chiara | Broekaart, Diede | Blarzino, Carla | Head, Elizabeth | Butterfield, D. Allan | Perluigi, Marzia
Article Type: Research Article
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. Show more
Keywords: Apoptosis, caspase, p53, sirtuins, Ts65Dn mouse model, trisomy 21
DOI: 10.3233/JAD-151105
Citation: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 359-371, 2016
Bach1 Overexpression in Down Syndrome Correlates with the Alteration of the HO-1/BVR-A System: Insights for Transition to Alzheimer's Disease
Authors: Di Domenico, Fabio | Pupo, Gilda | Mancuso, Cesare | Barone, Eugenio | Paolini, Francesca | Arena, Andrea | Blarzino, Carla | Schmitt, Frederick A. | Head, Elizabeth | Butterfield, D. Allan | Perluigi, Marzia
Article Type: Research Article
Abstract: Bach1, among the genes encoded on chromosome 21, is a transcription repressor, which binds to antioxidant response elements of DNA thus inhibiting the transcription of specific genes involved in the cell stress response including heme oxygenase-1 (HO-1). HO-1 and its partner, biliverdin reductase-A (BVR-A), are upregulated in response to oxidative stress in order to protect cells against further damage. Since oxidative stress is an early event in Down syndrome (DS) and might contribute to the development of multiple deleterious DS phenotypes, including Alzheimer's disease (AD) pathology, we investigated the status of the Bach1/HO-1/BVR-A axis in DS and its possible implications …for the development of AD. In the present study, we showed increased total Bach1 protein levels in the brain of all DS cases coupled with reduced induction of brain HO-1. Furthermore, increased oxidative stress could, on one hand, overcome the inhibitory effects of Bach1 and, on the other hand, promote BVR-A impairment. Our data show that the development of AD in DS subjects is characterized by (i) increased Bach1 total and poly-ubiquitination; (ii) increased HO-1 protein levels; and (iii) increased nitration of BVR-A followed by reduced activity. To corroborate our findings, we analyzed Bach1, HO-1, and BVR-A status in the Ts65Dn mouse model at 3 (young) and 15 (old) months of age. The above data support the hypothesis that the dysregulation of HO-1/BVR-A system contributes to the early increase of oxidative stress in DS and provide potential mechanistic paths involved in the neurodegenerative process and AD development. Show more
Keywords: Bach1, biliverdin reductase, heme oxygenase, oxidative stress, trisomy 21
DOI: 10.3233/JAD-141254
Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1107-1120, 2015