Oxidative Stress and Decreased Mitochondrial Superoxide Dismutase 2 and Peroxiredoxins 1 and 4 Based Mechanism of Concurrent Activation of AMPK and mTOR in Alzheimer’s Disease

Majd, Shohreh; Power, John H.

doi:10.2174/1567205015666180223093020

Cited by 49 publications

(37 citation statements)

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“…In particular, Prdx1 eliminates hydrogen peroxide produced during cellular metabolism [54] and participates in cell survival by enhancing the expression of the pro-survival factor protein kinase B (PKB) [55]. The role of Prdx1 in AD has been recently highlighted by Majd et al who observed reduced levels of Prdx1 and 2 in postmortem brains of AD [56]; meanwhile, Schreibelt et al analyzed the functional role of Prdx1 using a brain endothelial cell line overexpressing Prdx1 and showed that enhanced Prdx1 expression in brain endothelial cells increased BBB integrity and reduced monocyte adhesion to and migration across a brain endothelial cell layer [57]. …”

Section: Discussionmentioning

confidence: 99%

A Proteomic Approach to Uncover Neuroprotective Mechanisms of Oleocanthal against Oxidative Stress

Giusti

Angeloni

Barbalace

et al. 2018

IJMS

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Neurodegenerative diseases represent a heterogeneous group of disorders that share common features like abnormal protein aggregation, perturbed Ca2+ homeostasis, excitotoxicity, impairment of mitochondrial functions, apoptosis, inflammation, and oxidative stress. Despite recent advances in the research of biomarkers, early diagnosis, and pharmacotherapy, there are no treatments that can halt the progression of these age-associated neurodegenerative diseases. Numerous epidemiological studies indicate that long-term intake of a Mediterranean diet, characterized by a high consumption of extra virgin olive oil, correlates with better cognition in aged populations. Olive oil phenolic compounds have been demonstrated to have different biological activities like antioxidant, antithrombotic, and anti-inflammatory activities. Oleocanthal, a phenolic component of extra virgin olive oil, is getting more and more scientific attention due to its interesting biological activities. The aim of this research was to characterize the neuroprotective effects of oleocanthal against H2O2-induced oxidative stress in neuron-like SH-SY5Y cells. Moreover, protein expression profiling, combined with pathways analyses, was used to investigate the molecular events related to the protective effects. Oleocanthal was demonstrated to counteract oxidative stress, increasing cell viability, reducing reactive oxygen species (ROS) production, and increasing reduced glutathione (GSH) intracellular level. Proteomic analysis revealed that oleocanthal significantly modulates 19 proteins in the presence of H2O2. In particular, oleocanthal up-regulated proteins related to the proteasome, the chaperone heat shock protein 90, the glycolytic enzyme pyruvate kinase, and the antioxidant enzyme peroxiredoxin 1. Moreover, oleocanthal protection seems to be mediated by Akt activation. These data offer new insights into the molecular mechanisms behind oleocanthal protection against oxidative stress.

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Section: Discussionmentioning

confidence: 99%

A Proteomic Approach to Uncover Neuroprotective Mechanisms of Oleocanthal against Oxidative Stress

Giusti

Angeloni

Barbalace

et al. 2018

IJMS

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“…Alzheimer's disease (AD) is the leading cause of dementia worldwide, and AD patients and their families urgently require novel therapeutics to prevent and slow the progression of this devastating disorder. Hallmarks of AD include amyloid-␤ (A␤) peptide secretion and deposition into neuritic plaques, tau protein hyperphosphorylation and neurofibrillary tangle formation, metal ion dyshomeostasis [1][2][3][4][5][6][7][8][9], oxidative stress and lipid, nucleic acid, and protein damage [10][11][12][13], abortive cell cycle reentry [14][15][16][17][18][19][20][21][22][23][24][25][26], neuroinflammation and microbial dysbiosis [27][28][29][30][31][32][33], insulin resistance [34,35], cerebrovascular dysfunction [36][37][38], synaptic dysfunction [39,40], neuronal loss, endoplasmic reticulum stress [41][42][43][44], and mitochondrial dysfunction [...…”

Section: Introductionmentioning

confidence: 99%

“…PGC1␣ upregulates multiple antioxidant genes, including mitochondrial manganese superoxide dismutase (MnSOD), when bound to Forkhead box O3a (Foxo3a) and deacetylated by Sirtuin-1 (SIRT1) [69]. However, PGC1␣ protein levels are significantly lower in AD patients' hippocampi compared to controls [48], and mitochondrial biogenesis and MnSOD expression are impaired there [45,48]. Sildenafil has the potential to reverse the hippocampal PGC1␣ suppression in AD.…”

Section: Introductionmentioning

confidence: 99%

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Sanders

2020

ADR

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Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is upregulated. Sildenafil inhibits PDE5 and increases cGMP levels. Integrating previous findings, we determine that most doses of sildenafil (especially low doses) likely activate peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC1␣) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1␣ deacetylation. Via PGC1␣ signaling, low-dose sildenafil likely suppresses ␤-secretase 1 expression and amyloid-␤ (A␤) generation, upregulates antioxidant enzymes, and induces mitochondrial biogenesis. Plus, sildenafil should increase brain perfusion, insulin sensitivity, long-term potentiation, and neurogenesis while suppressing neural apoptosis and inflammation. A systematic review of sildenafil in AD was undertaken. In vitro, sildenafil protected neural mitochondria from A␤ and advanced glycation end products. In transgenic AD mice, sildenafil was found to rescue deficits in CREB phosphorylation and memory, upregulate brain-derived neurotrophic factor, reduce reactive astrocytes and microglia, decrease interleukin-1␤, interleukin-6, and tumor necrosis factor-␣, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested A␤ levels reported significant improvements except the two that used the highest dosage, consistent with the doselimiting effect of cGMP-induced phosphodiesterase 2 (PDE2) activation and cAMP depletion on PGC1␣ signaling. In AD patients, a single dose of sildenafil decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. A randomized control trial of sildenafil (ideally with a PDE2 inhibitor) in AD patients is warranted.

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“…Importantly, mitochondrial oxidative stress is directly associated with LC FR, and negatively affects neuronal viability leading to neurodegeneration (Sanchez-Padilla et al 2014). A key mitochondrial enzyme in this process is superoxide dismutase 2 (SOD2) which provides protection against AβO-mediated oxidative stress (Du et al 2019) and its expression is decreased in Alzheimer’s (Majd and Power 2018). We therefore assessed the association of AβO-NU1/2 expression with that of SOD2 in APP-PSEN1 mice.…”

Section: Resultsmentioning

confidence: 99%

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

Kelly

Seifi

et al. 2020

Preprint

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Amyloid β oligomers (AβO) are potent modulators of two key Alzheimer's pathological processes, namely synaptic dysfunction and tau tangle formation in various brain regions. Remarkably, the impact of AβO in one of the earliest brain regions to exhibit Alzheimer's pathology, the locus coeruleus (LC), remains to be determined. Of particular importance is the effect of AβO on the excitability of individual LC neurons. This parameter determines brain-wide noradrenaline (NA) release, and thus NA-mediated brain functions, including cognition, emotion and immune function, which are all severely compromised in Alzheimer's. Using a mouse model of increased Aβ production (APP-PSEN1), together with correlative histopathological analyses in post mortem Alzheimer's patient samples, we determined the impact of Aβ pathology on various correlates of LC neuronal integrity. AβO immunoreactivity in the LC of APP-PSEN1 mice was replicated in patient samples, presenting as individual clusters located both intraneuronally, in mitochondrial compartments, as well as extracellularly in association with inhibitory synapses. No specific signal was detected in either patient control or wild type mouse samples. Accompanying this AβO expression profile was LC neuronal hyperexcitability and indicators of oxidative stress in APP-PSEN1 mice. LC hyperexcitability arose from a diminished inhibitory effect of GABA, due to impaired expression and function of the GABA-A receptor (GABA A R) α 3 subunit. Importantly, this altered LCα 3-GABA A R expression profile overlapped with AβO expression in both APP-PSEN1 mice and Alzheimer's patient samples. Finally, strychninesensitive glycine receptors (GlyRs) remained resilient to AβO-induced changes and their activation reversed LC hyperexcitability. Alongside this first demonstration of 4 AβO expression in the LC of Alzheimer's patients, the study is also first to reveal a direct association between AβO and LC neuronal excitability. GlyR-α3-GABA A R modulation of AβO-dependent LC hyperexcitability could delay the onset of cognitive and psychiatric symptoms arising from LC-NA deficits, thereby significantly diminishing the disease burden for Alzheimer's patients. particular relevance to the LC, and its early presentation of Alzheimer's pathology, is the emerging synergistic role of AβO in tau tangle formation (Pickett et al. 2019; Shin et al. 2019b). Intriguingly, while notable LC neuronal loss, attributed to tauopathy, is a core feature in Alzheimer's (Chan-Palay and Asan 1989), there appears to be discordance between the onset of such pathology, and LC neurodegeneration (Weinshenker 2018). Given such considerable evidence, it is reasonable to speculate that in the LC, initial, pre-symptomatic insults in the form of tau tangle and AβO interactions, cooperate to set in motion a range of pathological changes such as synaptic dysfunction, oxidative stress (De Felice et al. 2007) and altered LC excitability (Sanchez-Padilla et al. 2014). Such changes are likely to prove crucial in terms of the long-term viabili...

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Oxidative Stress and Decreased Mitochondrial Superoxide Dismutase 2 and Peroxiredoxins 1 and 4 Based Mechanism of Concurrent Activation of AMPK and mTOR in Alzheimer’s Disease

Abstract: Collectively, we conclude that AMPK and mTOR metabolic axis is highly activated in AD brains. While the inhibitory link between AMPK and mTOR seems to be disrupted, we suggest oxidative stress as the underlying mechanism for concurrent activation of AMPK and mTOR in AD.

Cited by 49 publications

References 0 publications

A Proteomic Approach to Uncover Neuroprotective Mechanisms of Oleocanthal against Oxidative Stress

A Proteomic Approach to Uncover Neuroprotective Mechanisms of Oleocanthal against Oxidative Stress

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

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