Redox Signaling in Neurotransmission and Cognition During Aging

Kumar, Ashok; Yegla, Brittney; Foster, Thomas C.

doi:10.1089/ars.2017.7111

Cited by 77 publications

(53 citation statements)

References 306 publications

(391 reference statements)

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“…We have proposed that metabolic adaptation to a sedentary lifestyle impairs mitochondrial function with less energy for healthy management of amyloid and tau proteostasis, synaptic function, inflammation [18], ROS, and other stressors. This Epigenetic Oxidized Redox Shift (EORS) theory of aging postulates that an age-related oxidized redox shift causes a metabolic shift, epigenetic changes and a futile cycle of declining capacity with age [19,20]. Here, we hypothesize that these changes increase A␤ processing and intracellular aggregation.…”

Section: Introductionmentioning

confidence: 92%

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

Brewer¹,

Herrera

Philipp

et al. 2020

JAD

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This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iA␤), and the mechanism of an age-related increase in iA␤ in adult AD-model mouse neurons. A new end-specific antibody for A␤ 45 and another for aggregated forms of A␤ provide new insight into the composition of iA␤ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iA␤ levels containing aggregates of A␤ 45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iA␤ was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iA␤ and rapidly increased following a brief metabolic stress with glutamate. A␤PP-CTF, A␤ 45 , and aggregated A␤ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iA␤ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long A␤s by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iA␤ processing may lead to application of countermeasures to prolong dementia-free health span. human clinical trials [4]. Although gamma-secretase inhibitors were screened on the basis of their inhibition of the secretion of A␤, a detailed analysis of the mechanism indicated that Semagacestat slows the tripeptide carboxypeptidase terminal triming of the primary products of gamma-secretase endoproteolysis leading to the accumulation of "long A␤s" ending at residues 45, 46, 48, and 49 of the A␤ sequence (Fig. 1), similar to many of the FAD mutations in presenilin, which interfere with the processivity of the tripeptidase trimming [5][6][7]. These results suggest that the reason that Semagacestat and Avagacestat [8] caused cognitive worsening is the same reason that FAD mutations in presenilins cause early onset

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Section: Introductionmentioning

confidence: 92%

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

Brewer¹,

Herrera

Philipp

et al. 2020

JAD

View full text Add to dashboard Cite

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“…Oxidative stress is produced by the presence of unnecessary free radicals that are not neutralized by the antioxidant systems. It plays a vital pathological role in many chronic diseases and metabolic disorders, such as cancer [12,16], diabetes [17], cardiovascular disease [18], arthritis [19], ulcerative colitis [20], neural disorders [21], Alzheimer's disease [22], Parkinson's disease [23], cirrhosis [24], and aging [21]. Strengthening the antioxidant systems of the body by introducing antioxidants from outside sources can help eliminate excessive free radicals that cause oxidative stress, which impedes the progress of many oxidative stress-linked diseases.…”

Section: Introductionmentioning

confidence: 99%

Correlation between Antibacterial Activity and Free-Radical Scavenging: In-Vitro Evaluation of Polar/Non-Polar Extracts from 25 Plants

et al. 2020

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Objectives: The current study aimed to measure the antioxidant and antibacterial activities of 25 wild Palestinian edible plants, which were subjected to extraction by polar and non-polar solvents. Correlations between free radical scavenging activity and antibacterial activity of the extracts were assessed for both polar and non-polar fractions. Materials: Twenty-five wild edible plant species that are frequently consumed by people in Palestine (mainly in a rural area) were examined. Among them, 10 plant species were among those with the highest mean cultural importance values, according to an ethnobotanical survey that was conducted in the West Bank, Palestine, a few years ago. Method: The protocol of the DPPH assay for testing free-radical scavenging was utilized for determining EC50 values, while microdilution tests were conducted to determine the 50% inhibitory concentration (IC50) of the extracts for the microorganism Staphylococcus mutans. Results and Discussion: Eight extracts (non-polar fractions) were found to possess an antibacterial IC50 of less than 20 ppm, such as Foeniculum vulgare, Salvia palaestinafruticose, Micromeria fruticose, Trigonella foenum-graecum, Cichorium pumilum jacq, Salvia hierosolymitana boiss, Ruta chalepensis, and Chrysanthemum coronarium. The polar fractions possess higher antioxidant activity, while non-polar fraction possess higher antibacterial activity. Looking at all the results together can deceive and lead to the conclusion that there is no correlation between antibacterial activity against S. mutans and free radical scavenging (R2 equals 0.0538). However, in-depth analysis revealed that non-polar plant extracts with an EC50 of free radical scavenging ≤100 ppm have a four-fold order of enrichment toward more activity against S. mutans. These findings are of high importance for screening projects. A four-fold order of enrichment could save plenty of time and many in screening projects. The antibacterial active extracts marked by low-medium free radical scavenging might act through a mechanism of action other than that of highly active, free radical scavenging extracts. Conclusion: The screening of antioxidant and antimicrobial activity performed on 25 selected wild plant extracts revealed a satisfactory free radical scavenging and antimicrobial potential that could be of value in the management of oxidative stress. Further studies are recommended to explore novel and highly active natural antibacterial products.

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“…However, lessons from numerous preclinical investigations now rather support the view that impaired expression of NMDAR-dependent functional plasticity at synaptic connections is the major cellular substrate of physiological cognitive aging (Lynch, 1998 ; Barnes, 2003 ; Billard, 2006 ; Foster, 2012 ). A decrease in NMDAR density, and notably in GluN2B subunits, was initially suspected to underlie LTP deficits in the aging brain (Magnusson, 1998 , 2000 ; Clayton et al, 2002a , b ; Magnusson et al, 2002 ; Bai et al, 2004 ; Brim et al, 2013 ) but defects affecting the functional modulation of the receptor have also been later characterized including deregulation at the redox site (Kuehl-Kovarik et al, 2003 ; Bodhinathan et al, 2010 ; Yang et al, 2010 ; Kumar et al, 2017 ), changes in non-competitive blockade (Norris and Foster, 1999 ) and even altered lipid composition of postsynaptic membranes (Lynch and Voss, 1994 ; McGahon et al, 1999 ; Latour et al, 2013 ). In the search of such functional deficits, changes in SR-modulation of NMDAR activation has also been postulated to develop with age (Billard, 2013 ).…”

Section: Down Regulation Of Sr-related Activity In Physiological Aginmentioning

confidence: 99%

Changes in Serine Racemase-Dependent Modulation of NMDA Receptor: Impact on Physiological and Pathological Brain Aging

Billard

2018

Front. Mol. Biosci.

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The N-methyl-D-Aspartate glutamate receptors (NMDARs) are pivotal for the functional and morphological plasticity that are required in neuronal networks for efficient brain activities and notably for cognitive-related abilities. Because NMDARs are heterogeneous in subunit composition and associated with multiple functional regulatory sites, their efficacy is under the tonic influence of numerous allosteric modulations, whose dysfunction generally represents the first step generating pathological states. Among the enzymatic candidates, serine racemase (SR) has recently gathered an increasing interest considering that it tightly regulates the production of d-serine, an amino acid now viewed as the main endogenous co-agonist necessary for NMDAR activation. Nowadays, SR deregulation is associated with a wide range of neurological and psychiatric diseases including schizophrenia, amyotrophic lateral sclerosis, and depression. This review aims at compelling the most recent experimental evidences indicating that changes in SR-related modulation of NMDARs also govern opposite functional dysfunctions in physiological and pathological (Alzheimer's disease) aging that finally results in memory disabilities in both cases. It also highlights SR as a relevant alternative target for new pharmacological strategies aimed at preventing functional alterations and cognitive impairments linked to the aging process.

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Redox Signaling in Neurotransmission and Cognition During Aging

Cited by 77 publications

References 306 publications

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

Correlation between Antibacterial Activity and Free-Radical Scavenging: In-Vitro Evaluation of Polar/Non-Polar Extracts from 25 Plants

Changes in Serine Racemase-Dependent Modulation of NMDA Receptor: Impact on Physiological and Pathological Brain Aging

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