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Long-Term Pioglitazone Treatment Improves Learning and Attenuates Pathological Markers in a Mouse Model of Alzheimer's Disease
Open accessAbstract
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.
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“Pioglitazone, which belongs to the TZD class of compounds, has been shown to reduce the amyloid load in an ApoE and/ or IDE-dependent process, neurofibrillary tangle formation and decline in cognitive function in 3xTgAD mice (Mandrekar-Colucci et al., 2012; Mansour et al., 2021; Searcy et al., 2012; Zhong et al., 2023).”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Searcy et al., 2012
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“PPARγ has also been reported to reduce intraneuronal amyloid in APPV7171 and 3XTg mouse models of AD following Pioglitazone treatment4445.”
From Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease (2017) · cites this paper as [45]
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Metadata
- Authors
- Searcy, J. L., Phelps, J. T., Pancani, T., Kadish, I., Popovic, J., Anderson, K. L., Beckett, T. L., Murphy, M. P., Chen, K.-C., Blalock, E. M., Landfield, P. W., Porter, N. M., & Thibault, O.
- Affiliations
- University of Kentucky (US)
- University of Alabama at Birmingham (US)
- Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, KY, USA
- Corresponding author
- Thibault, Olivier
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2012-06-18
- Volume
- 30
- Issue
- 4
- Pages
- 943-961
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC3378773
- OpenAlex
- W1554596985
- Cited by
- 154
- References
- 113
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 8 · 2023: 6 · 2022: 8 · 2021: 17 · 2020: 11 · 2019: 9 · 2018: 10 · 2017: 13 · 2016: 14 · 2015: 18 · 2014: 16 · 2013: 10 · 2012: 3
- FWCI
- 10.08
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of California, Irvine
- National Institute on Aging (AG-029268, R21AG029268, P01AG010836, AG033649, AG020251, R01AG020251, AG010836, R01AG034605, AG034605, R01AG033649, R01AG037868)
- National Center for Research Resources (P20RR015592, P20RR15592)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- pioglitazone, thiazolidinediones
- MeSH terms
- Pioglitazone, Alzheimer Disease, Animals, Brain Chemistry, Disease Models, Animal, Drug Administration Schedule, Female, Learning, Mice, Transgenic, Time Factors, Biomarkers, Thiazolidinediones, Mice
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