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Authors: Gant, John C. | Kadish, Inga | Chen, Kuey-Chu | Thibault, Olivier | Blalock, Eric M. | Porter, Nada M. | Landfield, Philip W.

Article Type: Short Communication

Abstract: Aging is the leading risk factor for idiopathic Alzheimer’s disease (AD), indicating that normal aging processes promote AD and likely are present in the neurons in which AD pathogenesis originates. In AD, neurofibrillary tangles (NFTs) appear first in entorhinal cortex, implying that aging processes in entorhinal neurons promote NFT pathogenesis. Using electrophysiology and immunohistochemistry, we find pronounced aging-related Ca2 + dysregulation in rat entorhinal neurons homologous with the human neurons in which NFTs originate. Considering that humans recapitulate many aspects of animal brain aging, these results support the hypothesis that aging-related Ca2 + dysregulation occurs in human entorhinal neurons and …promotes NFT pathogenesis. Show more

Keywords: Afterhyperpolarization, aging models, calcium-dependent, cytoskeleton, FKBP, hippocampus, neurofibrillary progression, ryanodine receptor

DOI: 10.3233/JAD-180618

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1371-1378, 2018

Authors: Ghoweri, Adam O. | Gagolewicz, Peter | Frazier, Hilaree N. | Gant, John C. | Andrew, R. David | Bennett, Brian M. | Thibault, Olivier

Article Type: Research Article

Abstract: Background: Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer’s disease brain, including increases in amyloid-β, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear. Objective: Little is known about the temporal relationship between calcium dysregulation and oxidative stress, as some reports suggest that dysregulated calcium promotes increased formation of reactive oxygen species, while others support the opposite. Prior work has quantified several key outcome measures associated with …oxidative stress in aldehyde dehydrogenase 2 knockout (Aldh2 –/– ) mice, a non-transgenic model of sporadic Alzheimer’s disease. Methods: Here, we tested the hypothesis that early oxidative stress can promote calcium dysregulation across aging by measuring calcium-dependent processes using electrophysiological and imaging methods and focusing on the afterhyperpolarization (AHP), synaptic activation, somatic calcium, and long-term potentiation in the Aldh2 –/– mouse. Results: Our results show a significant age-related decrease in the AHP along with an increase in the slow AHP amplitude in Aldh2 –/– animals. Measures of synaptic excitability were unaltered, although significant reductions in long-term potentiation maintenance were noted in the Aldh2 –/– animals compared to wild-type. Conclusion: With so few changes in calcium and calcium-dependent processes in an animal model that shows significant increases in HNE adducts, Aβ, p-tau, and activated caspases across age, the current findings do not support a direct link between neuronal calcium dysregulation and uncontrolled oxidative stress. Show more

Keywords: Afterhyperpolarization, aging, calcium dysregulation, electrophysiology, hippocampus, HNE, intracellular, oxidative stress

DOI: 10.3233/JAD-200617

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1623-1637, 2020

Authors: Ghoweri, Adam O. | Ouillette, Lara | Frazier, Hilaree N. | Anderson, Katie L. | Lin, Ruei-Lung | Gant, John C. | Parent, Rachel | Moore, Shannon | Murphy, Geoffrey G. | Thibault, Olivier

Article Type: Research Article

Abstract: Background: In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer’s disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g., oxidation, amyloid-β production, and neuroinflammation). Further, neuronal calcium dysregulation is not always present in animal models of amyloidogenesis, questioning its reliability as a disease biomarker. Objective: Here, we directly tested for the presence of calcium dysregulation in dorsal hippocampal neurons in male and female 5×FAD mice on a …C57BL/6 genetic background using sharp electrodes coupled with Oregon-green Bapta-1 imaging. We focused on three ages that coincide with the course of amyloid deposition: 1.5, 4, and 10 months old. Methods: Outcome variables included measures of the afterhyperpolarization, short-term synaptic plasticity, and calcium kinetics during synaptic activation. Quantitative analyses of spatial learning and memory were also conducted using the Morris water maze. Main effects of sex, age, and genotype were identified on measures of electrophysiology and calcium imaging. Results: Measures of resting Oregon-green Bapta-1 fluorescence showed significant reductions in the 5×FAD group compared to controls. Deficits in spatial memory, along with increases in Aβ load, were detectable at older ages, allowing us to test for temporal associations with the onset of calcium dysregulation. Conclusion: Our results provide evidence that reduced, rather than elevated, neuronal calcium is identified in this 5×FAD model and suggests that this surprising result may be a novel biomarker of AD. Show more

Keywords: 5×FAD, afterhyperpolarization, aging, Alzheimer’s disease, calcium, electrophysiology, hippocampus, hyperactivity, intracellular, sex

DOI: 10.3233/JAD-200109

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1419-1438, 2020

Authors: Searcy, James L. | Phelps, Jeremiah T. | Pancani, Tristano | Kadish, Inga | Popovic, Jelena | Anderson, Katie L. | Beckett, Tina L. | Murphy, Michael P. | Chen, Kuey-Chu | Blalock, Eric M. | Landfield, Philip W. | Porter, Nada M. | Thibault, Olivier

Article Type: Research Article

Abstract: Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-γ) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipid profiles, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer's disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3xTg-AD) with accelerated amyloid-β (Aβ) deposition and tau pathology was treated with the …TZD pioglitazone (PIO-Actos® ) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal amyloid-β and tau deposits, and enhanced short- and long-term plasticity. Electrophysiological membrane properties and post-treatment blood glucose levels were unchanged by PIO. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes and decreases in glutamatergic and lipid metabolic/cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain. Show more

Keywords: 3xTg-AD, aging, hippocampus, long-term potentiation, microarray analysis, pioglitazone, PPAR, T2DM

DOI: 10.3233/JAD-2012-111661

Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 943-961, 2012