Low Dose Pioglitazone Attenuates Oxidative Damage in Early Alzheimer's Disease by Binding mitoNEET

2015 ◽  
Vol 5 (1) ◽  
pp. 24-45 ◽  
Author(s):  
Charles D. Hammack ◽  
George Perry ◽  
Richard G. LeBaron ◽  
Greg Villareal ◽  
Clyde F. Phelix
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidative Damage ◽  
Low Dose ◽  
Mitochondrial Protein ◽  
Central Component ◽  
Protein Levels ◽  
Early Alzheimer’S Disease ◽  
Peroxiredoxin 3

Oxidative damage (OD) is considered to be a central component in the progression of Alzheimer's disease (AD). 8-hydroxyguanosine (8-OHG), a readily oxidized ribonucleic acid found in AD, was used as a biomarker to investigate the role of OD in the progression of the disease. A disruption in two critical Thioredoxin-Dependent Peroxiredoxin System components, peroxiredoxin-3 (Prx-3) and thioredoxin (Trx), may serve as a source of the increased accumulation of OD observed in AD. We demonstrate that OD, in the form of 8-OHG, was quantitatively most significant during the earliest stage of AD [F (3, 25) = 5.08, p < .01]. A drastic decline in mitochondrial protein levels of Prx-3 [F (3, 25) = 8.74, p. < 01] and Trx [F (3, 25) = 4.33, p. < 05] were also observed across the progression of the disease. We then tested the efficacy of pioglitazone, a thiazolidinedione class drug aimed to delay onset of AD by acting on mitoNEET. Our results showed a significant reduction in the oxidized variant of mitoNEET within the incipient population when a 0.8mg dose was simulated in silico (p = 0.0242; a. < 05).

scholarly journals Investigating the role of neuronal oxidative stress in early Alzheimer’s disease pathology

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Morgan K. Foret ◽  
Sonia Do Carmo ◽  
Lindsay A. Welikovitch ◽  
Chiara Orciani ◽  
A. Claudio Cuello
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Alzheimer’S Disease

scholarly journals Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1353
Author(s):  
Francesca Romana Buccellato ◽  
Marianna D’Anca ◽  
Chiara Fenoglio ◽  
Elio Scarpini ◽  
Daniela Galimberti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidative Damage ◽  
Molecular Mechanisms ◽  
Biomarker Discovery ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Antioxidant Defenses ◽  
Ageing Population

Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

scholarly journals Elevated CLOCK and BMAL1 Contribute to the Impairment of Aerobic Glycolysis from Astrocytes in Alzheimer’s Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 7862
Author(s):  
Ik Dong Yoo ◽  
Min Woo Park ◽  
Hyeon Woo Cha ◽  
Sunmi Yoon ◽  
Napissara Boonpraman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Circadian Rhythm ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Over Expression ◽  
Protein Levels ◽  
Human Astrocytes ◽  
Altered Glucose

Altered glucose metabolism has been implicated in the pathogenesis of Alzheimer’s disease (AD). Aerobic glycolysis from astrocytes is a critical metabolic pathway for brain energy metabolism. Disturbances of circadian rhythm have been associated with AD. While the role of circadian locomotor output cycles kaput (CLOCK) and brain muscle ARNT-like1 (BMAL1), the major components in the regulation of circadian rhythm, has been identified in the brain, the mechanism by which CLOCK and BMAL1 regulates the dysfunction of astrocytes in AD remains unclear. Here, we show that the protein levels of CLOCK and BMAL1 are significantly elevated in impaired astrocytes of cerebral cortex from patients with AD. We demonstrate that the over-expression of CLOCK and BMAL1 significantly suppresses aerobic glycolysis and lactate production by the reduction in hexokinase 1 (HK1) and lactate dehydrogenase A (LDHA) protein levels in human astrocytes. Moreover, the elevation of CLOCK and BMAL1 induces functional impairment by the suppression of glial fibrillary acidic protein (GFAP)-positive filaments in human astrocytes. Furthermore, the elevation of CLOCK and BMAL1 promotes cytotoxicity by the activation of caspase-3-dependent apoptosis in human astrocytes. These results suggest that the elevation of CLOCK and BMAL1 contributes to the impairment of astrocytes by inhibition of aerobic glycolysis in AD.

scholarly journals RCAN1 Inhibits BACE2 Turnover by Attenuating Proteasome-Mediated BACE2 Degradation

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Kaixin Qiu ◽  
Shuai Wang ◽  
Xin Wang ◽  
Fengting Wang ◽  
Yili Wu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein A ◽  
Potential Mechanism ◽  
Neuritic Plaques ◽  
Protein Levels ◽  
Bace1 Expression ◽  
Main Component

Amyloid-β protein (Aβ) is the main component of neuritic plaques, the pathological hallmark of Alzheimer’s disease (AD). β-site APP cleaving enzyme 1 (BACE1) is a major β-secretase contributing to Aβ generation. β-site APP cleaving enzyme 2 (BACE2), the homolog of BACE1, is not only a θ-secretase but also a conditional β-secretase. Previous studies showed that regulator of calcineurin 1 (RCAN1) is markedly increased by AD and promotes BACE1 expression. However, the role of RCAN1 in BACE2 regulation remains elusive. Here, we showed that RCAN1 increases BACE2 protein levels. Moreover, RCAN1 inhibits the turnover of BACE2 protein. Furthermore, RCAN1 attenuates proteasome-mediated BACE2 degradation, but not lysosome-mediated BACE2 degradation. Taken together, our work indicates that RCAN1 inhibits BACE2 turnover by attenuating proteasome-mediated BACE2 degradation. It advances our understanding of BACE2 regulation and provides a potential mechanism of BACE2 dysregulation in AD.

scholarly journals Role of PrPC Expression in Tau Protein Levels and Phosphorylation in Alzheimer’s Disease Evolution

2014 ◽  
Vol 51 (3) ◽  
pp. 1206-1220 ◽  
Author(s):  
C. Vergara ◽  
L. Ordóñez-Gutiérrez ◽  
F. Wandosell ◽  
I. Ferrer ◽  
J. A. del Río ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Disease Evolution ◽  
Protein Levels

scholarly journals The role of navigation instruction at intersections for older drivers and those with early Alzheimer’s disease

2016 ◽  
Vol 96 ◽  
pp. 249-254 ◽  
Author(s):  
Laurence Paire-Ficout ◽  
Claude Marin-Lamellet ◽  
Sylviane Lafont ◽  
Catherine Thomas-Antérion ◽  
Bernard Laurent
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Older Drivers ◽  
Early Alzheimer’S Disease

scholarly journals Candidate Alzheimer’s Disease Biomarker miR-483-5p Lowers TAU Phosphorylation by Direct ERK1/2 Repression

2021 ◽  
Vol 22 (7) ◽  
pp. 3653
Author(s):  
Siranjeevi Nagaraj ◽  
Andrew Want ◽  
Katarzyna Laskowska-Kaszub ◽  
Aleksandra Fesiuk ◽  
Sara Vaz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Erk Pathway ◽  
Neurofibrillary Pathology ◽  
Protein Levels ◽  
Disease Biomarker ◽  
Extracellular Signal ◽  
Novel Target

MicroRNAs have been demonstrated as key regulators of gene expression in the etiology of a range of diseases including Alzheimer’s disease (AD). Recently, we identified miR-483-5p as the most upregulated miRNA amongst a panel of miRNAs in blood plasma specific to prodromal, early-stage Alzheimer’s disease patients. Here, we investigated the functional role of miR-483-5p in AD pathology. Using TargetScan and miRTarBase, we identified the microtubule-associated protein MAPT, often referred to as TAU, and the extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), known to phosphorylate TAU, as predicted direct targets of miR-483-5p. Employing several functional assays, we found that miR-483-5p regulates ERK1 and ERK2 at both mRNA and protein levels, resulting in lower levels of phosphorylated forms of both kinases. Moreover, miR-483-5p-mediated repression of ERK1/2 resulted in reduced phosphorylation of TAU protein at epitopes associated with TAU neurofibrillary pathology in AD. These results indicate that upregulation of miR-483-5p can decrease phosphorylation of TAU via ERK pathway, representing a compensatory neuroprotective mechanism in AD pathology. This miR-483-5p/ERK1/TAU axis thus represents a novel target for intervention in AD.

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