Antagonist of peroxisome proliferator-activated receptor γ induces cerebellar amyloid-β levels and motor dysfunction in APP/PS1 transgenic mice
Abstract
Recent evidences show that peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in the modulation of the amyloid-beta (Abeta) cascade causing Alzheimer's disease (AD) and treatment with PPARgamma agonists protects against AD pathology. However, the function of PPARgamma steady-state activity in Abeta cascade and AD pathology remains unclear. In this study, an antagonist of PPARgamma, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPARgamma activity in cerebellum. The results show that inhibition of PPARgamma significantly induced Abeta levels in cerebellum and caused cerebellar motor dysfunction in APP/PS1 transgenic mice. Moreover, GW9662 treatment markedly decreased the cerebellar levels of insulin-degrading enzyme (IDE), which is responsible for the cellular degradation of Abeta. Since cerebellum is spared from significant Abeta accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPARgamma steady-state activity in protection of cerebellum against AD pathology.
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“Previous work has also suggested that PPAR activation may regulate the expression of key Aβ proteases, insulin-degrading enzyme (IDE) and neprilysin (Du et al., 2009; Kalinin et al., 2009).”
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- Authors
- Du, J., Sun, B., Chen, K., Fan, L., & Wang, Z.
- Affiliations
- Tsinghua University (CN)
- Anhui Medical University (CN)
- Corresponding author
- Wang, Zhao
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 384
- Issue
- 3
- Pages
- 357-361
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2060644193
- Cited by
- 19
- References
- 22
- Citations by year
- 2024: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 2 · 2016: 2 · 2015: 2 · 2012: 5
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- PPARγ, GW9662, amyloid-beta, cerebellum, motor impairment, APP/PS1 mice, Alzheimer's disease, insulin-degrading enzyme, PPARγ antagonist
- MeSH terms
- Alzheimer Disease, Anilides, Animals, Cerebellum, Disease Models, Animal, Hippocampus, Mice, Transgenic, Motor Activity, Movement Disorders, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, PPAR gamma, Mice
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