Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice.

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-mediated transcription factors, which control both lipid and energy metabolism and inflammation pathways. PPARγ 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.

• Authors: Magali Dumont, Cliona Stack, Ceyhan Elipenahli, Shari Jainuddin, Meri Gerges, Natalia Starkova, Noel Y Calingasan, Lichuan Yang, Davide Tampellini, Anatoly A Starkov, Robin B Chan, Gilbert Di Paolo, Aurora Pujol, M Flint Beal
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 21 Issue 23 Pg. 5091-105 (Dec 01 2012) ISSN: 1460-2083 [Electronic] England
• PMID: 22922230 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• tau Proteins
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3
• Bezafibrate

Topics

• Adipose Tissue, Brown (drug effects, metabolism)
• Animals
• Behavior, Animal (drug effects)
• Bezafibrate (administration & dosage, pharmacology)
• Disease Models, Animal
• Energy Metabolism (drug effects)
• Fatty Acids (metabolism)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Inflammation (drug therapy, metabolism, pathology)
• Mice
• Mice, Transgenic
• Oxidation-Reduction
• Oxidative Stress
• Phosphorylation (drug effects)
• Tauopathies (drug therapy, metabolism)
• tau Proteins (metabolism)