Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. PPAR agonists have well-documented anti-inflammatory and neuroprotective roles in the central nervous system. Recent evidence suggests that PPAR agonists are attractive therapeutic agents for treating neurodegenerative diseases as well as addiction. However, the distribution of PPAR mRNA and protein in brain regions associated with these conditions (i.e. prefrontal cortex, nucleus accumbens, amygdala, ventral tegmental area) is not well defined. Moreover, the cell type specificity of PPARs in mouse and human brain tissue has yet to be investigated. We utilized quantitative PCR and double immunofluorescence microscopy to determine that both PPAR mRNA and protein are expressed ubiquitously throughout the adult mouse brain. We found that PPARs have unique cell type specificities that are consistent between species. PPARα was the only isotype to colocalize with all cell types in both adult mouse and adult human brain tissue. Overall, we observed a strong neuronal signature, which raises the possibility that PPAR agonists may be targeting neurons rather than glia to produce neuroprotection. Our results fill critical gaps in PPAR distribution and define novel cell type specificity profiles in the adult mouse and human brain.
Highlights
The presence of the different Peroxisome proliferator-activated receptors (PPARs) isotypes in specific cell types is still somewhat conflicting, in particular for astrocytes and microglia
Given that PPAR agonists are being tested in human clinical trials, it is surprising that there are no cell type specificity profiles defined for PPAR isotypes in human brain tissue
The PPARγagonist pioglitazone has been used in two small human trials, which found that pioglitazone administration resulted in cognitive and functional improvements in Alzheimer’s patients[33,34]
Summary
The presence of the different PPAR isotypes in specific cell types is still somewhat conflicting, in particular for astrocytes and microglia. The success of PPAR agonists to produce neuroprotective changes in a brain region-dependent manner necessitates an enhanced understanding of PPAR isotype cell type specificity in brain tissue. The aim of this present work was to fill critical gaps in PPAR expression data by providing a more detailed distribution map of PPAR isotype mRNA and protein in specific brain regions that are implicated in neurodegenerative diseases and addiction. The strong neuronal signature of all PPAR isotypes was surprising and suggests a new role for PPAR agonists in targeting neurons rather than glial cells These findings will enable future studies to select cell type specific PPAR agonists to provide targeted neuroprotective treatments for neurodegenerative diseases
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