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Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice

Dumont, Magali; Stack, Cliona; Elipenahli, Ceyhan; Jainuddin, Shari; Gerges, Meri; Starkova, Natalia; Calingasan, Noel Y.; Yang, Lichuan; Tampellini, Davide LU and Starkov, Anatoly A., et al. (2012) In Human Molecular Genetics 21(23). p.5091-5105
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-mediated transcription factors, which control both lipid and energy metabolism and inflammation pathways. PPAR agonists are effective in the treatment of metabolic diseases and, more recently, neurodegenerative diseases, in which they show promising neuroprotective effects. We studied the effects of the pan-PPAR agonist bezafibrate on tau pathology, inflammation, lipid metabolism and behavior in transgenic mice with the P301S human tau mutation, which causes familial frontotemporal lobar degeneration. Bezafibrate treatment significantly decreased tau hyperphosphorylation using AT8 staining and the number of MC1-positive neurons. Bezafibrate treatment also diminished microglial... (More)
Peroxisome proliferator-activated receptors (PPARs) are ligand-mediated transcription factors, which control both lipid and energy metabolism and inflammation pathways. PPAR agonists are effective in the treatment of metabolic diseases and, more recently, neurodegenerative diseases, in which they show promising neuroprotective effects. We studied the effects of the pan-PPAR agonist bezafibrate on tau pathology, inflammation, lipid metabolism and behavior in transgenic mice with the P301S human tau mutation, which causes familial frontotemporal lobar degeneration. Bezafibrate treatment significantly decreased tau hyperphosphorylation using AT8 staining and the number of MC1-positive neurons. Bezafibrate treatment also diminished microglial activation and expression of both inducible nitric oxide synthase and cyclooxygenase 2. Additionally, the drug differentially affected the brain and brown fat lipidome of control and P301S mice, preventing lipid vacuoles in brown fat. These effects were associated with behavioral improvement, as evidenced by reduced hyperactivity and disinhibition in the P301S mice. Bezafibrate therefore exerts neuroprotective effects in a mouse model of tauopathy, as shown by decreased tau pathology and behavioral improvement. Since bezafibrate was given to the mice before tau pathology had developed, our data suggest that bezafibrate exerts a preventive effect on both tau pathology and its behavioral consequences. Bezafibrate is therefore a promising agent for the treatment of neurodegenerative diseases associated with tau pathology. (Less)
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publication status
published
subject
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Human Molecular Genetics
volume
21
issue
23
pages
5091 - 5105
publisher
Oxford University Press
external identifiers
  • wos:000310967900006
  • scopus:84869070404
ISSN
0964-6906
DOI
10.1093/hmg/dds355
language
English
LU publication?
yes
id
95c1bff4-3efe-4447-99e3-1440324f41fc (old id 3379451)
date added to LUP
2013-02-01 07:02:40
date last changed
2017-10-22 03:31:53
@article{95c1bff4-3efe-4447-99e3-1440324f41fc,
  abstract     = {Peroxisome proliferator-activated receptors (PPARs) are ligand-mediated transcription factors, which control both lipid and energy metabolism and inflammation pathways. PPAR agonists are effective in the treatment of metabolic diseases and, more recently, neurodegenerative diseases, in which they show promising neuroprotective effects. We studied the effects of the pan-PPAR agonist bezafibrate on tau pathology, inflammation, lipid metabolism and behavior in transgenic mice with the P301S human tau mutation, which causes familial frontotemporal lobar degeneration. Bezafibrate treatment significantly decreased tau hyperphosphorylation using AT8 staining and the number of MC1-positive neurons. Bezafibrate treatment also diminished microglial activation and expression of both inducible nitric oxide synthase and cyclooxygenase 2. Additionally, the drug differentially affected the brain and brown fat lipidome of control and P301S mice, preventing lipid vacuoles in brown fat. These effects were associated with behavioral improvement, as evidenced by reduced hyperactivity and disinhibition in the P301S mice. Bezafibrate therefore exerts neuroprotective effects in a mouse model of tauopathy, as shown by decreased tau pathology and behavioral improvement. Since bezafibrate was given to the mice before tau pathology had developed, our data suggest that bezafibrate exerts a preventive effect on both tau pathology and its behavioral consequences. Bezafibrate is therefore a promising agent for the treatment of neurodegenerative diseases associated with tau pathology.},
  author       = {Dumont, Magali and Stack, Cliona and Elipenahli, Ceyhan and Jainuddin, Shari and Gerges, Meri and Starkova, Natalia and Calingasan, Noel Y. and Yang, Lichuan and Tampellini, Davide and Starkov, Anatoly A. and Chan, Robin B. and Di Paolo, Gilbert and Pujol, Aurora and Beal, M. Flint},
  issn         = {0964-6906},
  language     = {eng},
  number       = {23},
  pages        = {5091--5105},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice},
  url          = {http://dx.doi.org/10.1093/hmg/dds355},
  volume       = {21},
  year         = {2012},
}