The Triangle of Death in Alzheimer's Disease Brain: The Aberrant Cross-Talk Among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics

Domenico, Fabio Di; Barone, Eugenio; Perluigi, Marzia; Butterfield, D. Allan

doi:10.1089/ars.2016.6759

Cited by 96 publications

(64 citation statements)

References 260 publications

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“…Focusing more on the energy metabolism it has been shown that the severity of disease is associated with progressive alterations in brain metabolism [1] of AD patients. These alterations comprise manifold cellular and molecular changes [2] for example glucose hypometabolism [3–5] and a reduction in the gene expression [6], protein level and activity [7, 8] of mitochondrial proteins. Taking into account the abundance of metabolic disturbances as early as in mild cognitive impairment [9] and the detrimental effects of the resulting energy imbalance on neuronal health, AD can be regarded as a fundamentally metabolic disease [10].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration

et al. 2016

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One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), increasing APP and Aβ levels or Aβ alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Aβ levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Aβ-mediated mitochondrial toxicity. Analyzing Aβ localization revealed that intracellular levels of Aβ and an increased spatial association of APP/Aβ with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Aβ accumulation in Alzheimer´s disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration

et al. 2016

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“…Indeed, protein levels of translation initiation factors eIF2α, eIF3η and eIF5, and elongation factor eEF2, are altered in the CA1 region in AD [79]. Additionally, increased phosphorylation of the mammalian (mechanistic) target of rapamycin (mTOR), a protein kinase phosphorylating a wide spectrum of intracellular proteins, may also promote inhibition of protein synthesis in AD [80]. It is possible that mTOR phosphorylates the elongation factor 1A (EF1A), a crucial translation factor mediating peptide elongation by promoting GTP-dependent binding of aminoacyl tRNA to the ribosome, and eIF2α and thus, inhibits protein synthesis.…”

mentioning

confidence: 99%

Cholinergic degeneration in early stages of Alzheimer’s disease: Loss of cholinergic phenotype or loss of cells?

Stepanichev¹,

Nedogreeva²,

Gulyaeva³

2017

Alzheimers Dement Cogn Neurol

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“…Of note, a recent study by Han et al [27] did not report increased mTOR levels in HA-1800 cells challenged with Ab 1-42 oligomers and insulin, leaving room for further investigation. In synthesis, reduced glucose utilization is associated with the buildup of Ab as mediated by over-activated mTOR [48], even though the precise nature of this relation needs to be clarified. Nevertheless, HT prevented the pronounced activation of mTOR in Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) astrocytes, which suggests that HT protects the Ab(25-35)blocked insulin signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that inhibits insulin signaling by phosphorylating IRS-1 serine residues [47]. Recent studies have shown that mTOR is aberrantly activated in AD brain, which is linked to the insulin signaling inhibition [48]. Because Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) induces IR in astrocytes, we wanted to resolve whether Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) promoted this resistance through an over-activation of mTOR.…”

Section: Ht Restores Proper Akt Activation In Ab(25-35)-treated Astromentioning

confidence: 99%

Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease

et al. 2017

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Recent epidemiological evidence demonstrated that diabetes is a risk factor for AD onset and development. Indeed, meta-analyses of longitudinal epidemiologic studies show that diabetes increases AD risk by 50-100%, being insulin resistance (IR) the main binding link between diabetes and AD. Astrocytes are the foremost cerebral macroglial cells and are responsible for converting glucose into lactate and transfer it to neurons that use it as fuel, but Aβ(1-42) impairs insulin signaling and glycogen storage. Recent prospective studies showed that the Mediterranean diet is associated with lower incidence of AD. We hypothesized that hydroxytyrosol (HT, the preeminent polyphenol of olives and olive oil) could exert beneficial effects on IR associated with AD and investigated it mechanisms of action in an astrocytic model of AD. The astrocytic cell line C6 was exposed to Aβ(25-35) and co-incubated with HT for different periods. After treatment with Aβ(25-35), astrocytes' viability was significantly decreased as compared with controls; however, both pre- and post-treatment with HT prevented this effect. Mechanistically, we found that the preventive role of HT on Aβ(25-35)- induced cytotoxicity in astrocytes is moderated by an increased HT-induced activation of Akt, which is mediated by the insulin signaling pathway. In addition, we report that HT prevented the pronounced activation of mTOR, thereby restoring proper insulin signaling. In conclusion, we demonstrate that HT protects Aβ(25-35)-treated astrocytes by improving insulin sensitivity and restoring proper insulin-signaling. These data provide some mechanistic insight on the observed inverse association between olive oil consumption and prevalence of cognitive impairment. © 2017 BioFactors, 43(4):540-548, 2017.

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The Triangle of Death in Alzheimer's Disease Brain: The Aberrant Cross-Talk Among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics

Abstract: The identification of compounds able to restore the function of the pathways targeted by oxidative damage might represent a valuable therapeutic approach to slow or delay AD. Antioxid. Redox Signal. 26, 364-387.

Cited by 96 publications

References 260 publications

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration

Cholinergic degeneration in early stages of Alzheimer’s disease: Loss of cholinergic phenotype or loss of cells?

Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease

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