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.

The impact of chronic stress on the rat brain lipidome

“…Tissue lipid extracts were prepared using a modified Bligh/Dyer procedure, spiked with appropriate internal standards, and analyzed using a 6490 Triple Quadrupole LC/MS system (Agilent Technologies, Santa Clara, CA). Glycerophospholipids and sphingolipids were separated with normal-phase HPLC as before 17, 18 , with a few changes. An Agilent Zorbax Rx-Sil column (inner diameter 2.1 × 100 mm) was used under the following conditions: mobile phase A (chloroform:methanol:1 M ammonium hydroxide, 89.9:10:0.1, v/v) and mobile phase B (chloroform:methanol:water:ammonium hydroxide, 55:39.9:5:0.1, v/v); 95% A for 2 min, linear gradient to 30% A over 18 min and held for 3 min, and linear gradient to 95% A over 2 min and held for 6 min.…”

Mitochondrial Quality Control as a Therapeutic Target

“…In a mouse model of AD (P301S transgenic mice) bezafibrate decreased disease progression by diminishing locomotor and stress-related abnormalities (Dumont et al, 2012;Noe et al, 2013). A modest increase in mitochondrial proliferation was noted, but mild increases in mtDNA content and Sirt1 and Tfam gene expression was more apparent in brown fat with increased expression of NRF1 and PGC-1a.…”

Trends in Mitochondrial Therapeutics for Neurological Disease

“…Bezafibrate, however, failed to induce mitochondrial biogenesis in other COX deficient models [101], in contrast with PGC-1α overexpression or its indirect activation with the AMPK agonist AICAR [102]. Still, bezafibrate restored PGC-1α levels, induced mitochondrial biogenesis, and exerted neuroprotective effects in mouse models of either HD [103] or tau pathology [104]. Moreover, bezafibrate increased mitochondrial proteins and ATP generating capacity, being neuroprotective in a mouse model of mitochondrial encephalopathy [105].…”