Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome

Tramutola, Antonella; Lanzillotta, Chiara; Arena, Andrea; Barone, Eugenio; Perluigi, Marzia; Domenico, Fabio Di

doi:10.1159/000441419

Cited by 36 publications

(42 citation statements)

References 35 publications

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“…Consistent with these studies, we previously showed decreased proteosomal activity in DS brain [22, 36]. This is associated with a significant decrease in a marker of autophagosome formation (LC3 II/I) both in DS and in the Ts65Dn mouse at 6mo [9, 37]. In addition, our group and others demonstrated that the overexpression of some of the genes onHSA21(chromosome 16 in mice), such as SOD1, APP, or bach1, might lead to increased “subchronic” levels of oxidative stress in DS individuals as well as in mouse models of DS/AD pathology triggering UPR activation [31, 38, 39].…”

Section: Discussionsupporting

confidence: 72%

Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models

Lanzillotta

Tramutola

Meier

et al. 2018

JAD

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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.

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Section: Discussionsupporting

confidence: 72%

Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models

Lanzillotta

Tramutola

Meier

et al. 2018

JAD

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“…Autophagy is inhibited both in DS and in AD (Liu et al 2009; Perluigi et al 2015; Tramutola et al 2016), and loss of normal autophagic function contributes to AD pathogenesis ( see also Nixon et al in the current Special Issue ). Other groups have shown that not only autophagy, but also endosomal pathways, are hampered in both DS and AD, resulting in enlargement of early endosomes that significantly affects protein trafficking in the cytosol (Cataldo et al 2000; Cossec et al 2012) and may also ultimately affect the secretion and cargo of exosomes, as autophagy has been implicated in endosome/exosome secretory pathways (Papandreou and Tavernarakis 2017).…”

Section: Introductionmentioning

confidence: 92%

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Hamlett

Ledreux

Potter³

et al. 2018

Free Radical Biology and Medicine

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Every person with Down syndrome (DS) has the characteristic features of Alzheimer’s disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood. We also found that the relative levels of these biomarkers were altered following dementia onset. Exosome release and signaling are dependent on cellular redox homeostasis as well as on inflammatory processes, and exosomes may be involved in the immune response, suggesting a dual role as both triggers of inflammation in the brain and propagators of inflammatory signals between brain regions. Based on recently reported connections between inflammatory processes and exosome release, the elevated neuroinflammatory state observed in people with DS may affect exosomal AD biomarkers. Herein, we discuss findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS showing new connections between neuroinflammatory pathways, oxidative stress, exosomes, and exosome-mediated signaling, which may inform future AD diagnostics, preventions, and treatments in the DS population as well as in the general population.

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“…Increased LPO products such as 8,12-iso-iPF2alpha-VI are observed both in the cortex and hippocampus of very young mice (2 months) [82], whereas increased HNE levels are found in the hippocampus of both 6- and 12-months olds mice [83]. HNE levels in very young mice have yet to be reported, but the increase of other LPO products could suggest an increase of HNE as well.…”

Section: Hne-modified Proteins Contribute To Neurodegeneration In mentioning

confidence: 99%

“…Indeed, administration of α-tocopherol to pregnant Ts65Dn females from the day of conception throughout the pregnancy prevented the increase in LPO [83]. Furthermore, Gulesserian et al found a significant reduction in levels of glutathione synthetase, glutathione-S-transferase and thioredoxin peroxidase-I and -II in DS fetal brain compared with controls, thus supporting an early impairment of GSH pathway which may contribute to the observed increase in LPO [26].…”

Section: Hne-modified Proteins Contribute To Neurodegeneration In mentioning

confidence: 99%

“…The analysis of mTOR expression and phosphorylation in the hippocampus of Ts65Dn mice shows an aberrant activation of mTOR signaling starting at 6 months, which persists to 12 months of age supporting a genotype-dependent alteration of the pathway. As a result of aberrant mTOR signaling, autophagosome formation is reduced in Ts65Dn mice compared with euploid mice at both 6 and 12 months of age, suggesting its possible involvement in an increase in oxidative damage in Ts65Dn mice [83]. …”

Section: Hne-modified Proteins Contribute To Neurodegeneration In mentioning

confidence: 99%

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HNE-modified proteins in Down syndrome: Involvement in development of Alzheimer disease neuropathology

Barone

Head

Butterfield

et al. 2017

Free Radical Biology and Medicine

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Down syndrome (DS), trisomy of chromosome 21, is the most common genetic form of intellectual disability. The neuropathology of DS involves multiple molecular mechanisms, similar to AD, including the deposition of beta-amyloid (Aβ) into senile plaques and tau hyperphosphorylating in neurofibrillary tangles. Interestingly, many genes encoded by chromosome 21, in addition to being primarily linked to amyloid-beta peptide (Aβ) pathology, are responsible for increased oxidative stress (OS) conditions that also result as a consequence of reduced antioxidant system efficiency. However, redox homeostasis is disturbed by overproduction of Aβ, which accumulates into plaques across the lifespan in DS as well as in AD, thus generating a vicious cycle that amplifies OS-induced intracellular changes. The present review describes the current literature that demonstrates the accumulation of oxidative damage in DS with a focus on the lipid peroxidation by-product, 4-hydroxy-2-nonenal (HNE). HNE reacts with proteins and can irreversibly impair their functions. We suggest that among different post-translational modifications, HNE-adducts on proteins accumulate in DS brain and play a crucial role in causing the impairment of glucose metabolism, neuronal trafficking, protein quality control and antioxidant response. We hypothesize that dysfunction of these specific pathways contribute to accelerated neurodegeneration associated with AD neuropathology.

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Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome

Cited by 36 publications

References 35 publications

Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models

Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models

Exosomal biomarkers in Down syndrome and Alzheimer's disease

HNE-modified proteins in Down syndrome: Involvement in development of Alzheimer disease neuropathology

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