Changes in Glutathione Redox Potential Are Linked to Aβ42-Induced Neurotoxicity

Stapper, Zeenna A.; Jahn, Thomas R.

doi:10.1016/j.celrep.2018.07.052

Cited by 22 publications

(26 citation statements)

References 26 publications

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“…This is very important since dendritic spines are critical for synaptic function, including synaptic plasticity. Our results are in agreement with other studies that have shown the presence of increased S-glutathionylation of specific proteins in AD patients and mouse models (3,41,56,70). Studies with human postmortem AD frontal cortex tissues suggest that oxidative stress is an early feature and plays a critical role in AD…”

Section: Discussionsupporting

confidence: 93%

Glutaredoxin1 Diminishes Amyloid Beta-Mediated Oxidation of F-Actin and Reverses Cognitive Deficits in an Alzheimer's Disease Mouse Model

Kommaddi

Tomar

Karunakaran

et al. 2019

Antioxidants & Redox Signaling

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Aims: Reactive oxygen species (ROS) generated during Alzheimer's disease (AD) pathogenesis through multiple sources are implicated in synaptic pathology observed in the disease. We have previously shown Factin disassembly in dendritic spines in early AD (34). The actin cytoskeleton can be oxidatively modified resulting in altered F-actin dynamics. Therefore, we investigated whether disruption of redox signaling could contribute to actin network disassembly and downstream effects in the amyloid precursor protein/presenilin-1 double transgenic (APP/PS1) mouse model of AD. Results: Synaptosomal preparations from 1-month-old APP/PS1 mice showed an increase in ROS levels, coupled with a decrease in the reduced form of F-actin and increase in glutathionylated synaptosomal actin. Furthermore, synaptic glutaredoxin 1 (Grx1) and thioredoxin levels were found to be lowered. Overexpressing Grx1 in the brains of these mice not only reversed F-actin loss seen in APP/PS1 mice but also restored memory recall after contextual fear conditioning. F-actin levels and F-actin nanoarchitecture in spines were also stabilized by Grx1 overexpression in APP/PS1 primary cortical neurons, indicating that glutathionylation of Factin is a critical event in early pathogenesis of AD, which leads to spine loss. Innovation: Loss of thiol/disulfide oxidoreductases in the synapse along with increase in ROS can render Factin nanoarchitecture susceptible to oxidative modifications in AD. Conclusions: Our findings provide novel evidence that altered redox signaling in the form of S-glutathionylation and reduced Grx1 levels can lead to synaptic dysfunction during AD pathogenesis by directly disrupting the Factin nanoarchitecture in spines. Increasing Grx1 levels is a potential target for novel disease-modifying therapies for AD.

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Section: Discussionsupporting

confidence: 93%

Glutaredoxin1 Diminishes Amyloid Beta-Mediated Oxidation of F-Actin and Reverses Cognitive Deficits in an Alzheimer's Disease Mouse Model

Kommaddi

Tomar

Karunakaran

et al. 2019

Antioxidants & Redox Signaling

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“…Notably, we demonstrate that the two cysteine residues of full-length tau act as key mediators of this phenotype, thereby identifying a novel cis -element governing the unconventional secretion of tau. Therefore, we suggest that the disease-associated redox disturbances in physiological cellular homeostasis might not only be a source of neuronal damage 78 , but they could in turn drive and promote the trans-cellular propagation of tau. Most importantly, such efforts for the in-depth characterization of the molecular mechanisms involved in the initiation and progression of the disease-related pathology will provide a stepping stone in the design of therapeutic approaches against neurodegeneration.…”

Section: Discussionmentioning

confidence: 98%

Identification of cis-acting determinants mediating the unconventional secretion of tau

Katsinelos

McEwan

Jahn

et al. 2021

Sci Rep

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The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer’s disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis-elements that are important for both unconventional secretion and trans-cellular propagation of tau.

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“…In humans, this decline occurs rapidly after age 45 (Imai and Guarente, 2014). The consequences of a decline in NAD + levels could be compromised mitochondrial energy production and impairment of the clearance of damaged mitochondria (Papa and Germain, 2017), along with a diminished capacity of the brain's response to oxidative stress (Kharrazi et al, 2008;Maruszak et al, 2011;Chico et al, 2013;Das et al, 2018;Liguori et al, 2018;Stapper and Jahn, 2018). States of intensive compensatory energy metabolism would lead to the production of ROS, which increase in an age-dependent fashion within the mitochondria (Kuka et al, 2013) with subsequent toxic effects damaging proteins, lipids, and DNA, eventually resulting in neuronal death.…”

Section: Identification Of Bioenergetic and Metabolic Alterations In Load Cells As A Function Of Cell Type Development Genetic Backgroundmentioning

confidence: 99%

Hypothesis and Theory: Characterizing Abnormalities of Energy Metabolism Using a Cellular Platform as a Personalized Medicine Approach for Alzheimer’s Disease

Ryu

Cohen

Sonntag

2021

Front. Cell Dev. Biol.

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Sporadic or late-onset Alzheimer’s disease (LOAD) is characterized by slowly progressive deterioration and death of CNS neurons. There are currently no substantially disease-modifying therapies. LOAD pathology is closely related to changes with age and include, among others, accumulation of toxic molecules and altered metabolic, microvascular, biochemical and inflammatory processes. In addition, there is growing evidence that cellular energy deficits play a critical role in aging and LOAD pathophysiology. However, the exact mechanisms and causal relationships are largely unknown. In our studies we tested the hypothesis that altered bioenergetic and metabolic cell functions are key elements in LOAD, using a cellular platform consisting of skin fibroblasts derived from LOAD patients and AD-unaffected control individuals and therefrom generated induced pluripotent stem cells that are differentiated to brain-like cells to study LOAD pathogenic processes in context of age, disease, genetic background, cell development, and cell type. This model has revealed that LOAD cells exhibit a multitude of bioenergetic and metabolic alterations, providing evidence for an innate inefficient cellular energy management in LOAD as a prerequisite for the development of neurodegenerative disease with age. We propose that this cellular platform could ultimately be used as a conceptual basis for a personalized medicine tool to predict altered aging and risk for development of dementia, and to test or implement customized therapeutic or disease-preventive intervention strategies.

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Changes in Glutathione Redox Potential Are Linked to Aβ42-Induced Neurotoxicity

Cited by 22 publications

References 26 publications

Glutaredoxin1 Diminishes Amyloid Beta-Mediated Oxidation of F-Actin and Reverses Cognitive Deficits in an Alzheimer's Disease Mouse Model

Glutaredoxin1 Diminishes Amyloid Beta-Mediated Oxidation of F-Actin and Reverses Cognitive Deficits in an Alzheimer's Disease Mouse Model

Identification of cis-acting determinants mediating the unconventional secretion of tau

Hypothesis and Theory: Characterizing Abnormalities of Energy Metabolism Using a Cellular Platform as a Personalized Medicine Approach for Alzheimer’s Disease

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