Cited by 154Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Long-Term Pioglitazone Treatment Improves Learning and Attenuates Pathological Markers in a Mouse Model of Alzheimer's Disease

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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·2012·Journal of Alzheimer's Disease

DOI 10.3233/jad-2012-111661PMC PMC3378773

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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.

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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
ORCID: Anderson, Katie L.
Blalock, Eric M.
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
DOI: 10.3233/jad-2012-111661
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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Long-Term Pioglitazone Treatment Improves Learning and Attenuates Pathological Markers in a Mouse Model of Alzheimer's Disease

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