Divergent Mechanisms for PPARγ Agonism in Ameliorating Aging-Related Versus Cranial Irradiation-Induced Context Discrimination Deficits.

Ibdanelo Cortez,Kelly T Dineley,Larry Denner

doi:10.3389/fnagi.2019.00038

Ibdanelo Cortez, Kelly T Dineley + Show 1 more

Open Access

https://doi.org/10.3389/fnagi.2019.00038

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Abstract

A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors in a process termed neurogenesis. Adult neurogenesis is limited to specific brain regions in the mammalian brain, such as the subgranular zone (SGZ) of the hippocampus. Alterations in adult neurogenesis appear to be a common hallmark in different neurodegenerative diseases including Alzheimer’s disease (AD). We and others have shown that PPARγ agonism improves cognition in preclinical models of AD as well as in several pilot clinical trials. Context discrimination is recognized as a cognitive task supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus that we and others have previously shown declines with age. We therefore postulated that PPARγ agonism would positively impact context discrimination in middle-aged mice via mechanisms that influence proliferation and differentiation of adult-born neurons arising from the SGZ. To achieve our objective, 8-months old mice were left untreated or treated with the FDA-approved PPARγ agonist, rosiglitazone then tested for context discrimination learning and memory, followed by immunofluorescence evaluation of hippocampal SGZ cell proliferation and neuron survival. We found that PPARγ agonism enhanced context discrimination performance in middle-aged mice concomitant with stimulated SGZ cell proliferation, but not new neuron survival. Focal cranial irradiation that destroys neurogenesis severely compromised context discrimination in middle-aged mice yet rosiglitazone treatment significantly improved cognitive performance through an anti-inflammatory mechanism and resurrection of the neurogenic niche. Thus, we have evidence for divergent mechanisms by which PPARγ agonism impinges upon aging-related versus cranial irradiation-induced deficits in context discrimination learning and memory.

Highlights

MATERIALS AND METHODSThe Peroxisome Proliferator-activated Receptor gamma (PPARγ) is a ligand-modulated nuclear transcription factor and a therapeutic target for treating insulin resistance in type-2 diabetes patients
To determine if PPARγ agonism influences context discrimination via a neurogenesis-dependent manner with and without focal cranial irradiation, we tested our groups in a context fear discrimination memory task (Figure 3)
We found that PPARγ agonism enhanced context discrimination performance in middle-aged mice concomitant with stimulated subgranular zone (SGZ) cell proliferation (24 h BrdU incorporation and Ki67 staining), but not new neuron survival (45 dpi BrdU incorporation, doublecortin staining)

Summary

Introduction

MATERIALS AND METHODSThe Peroxisome Proliferator-activated Receptor gamma (PPARγ) is a ligand-modulated nuclear transcription factor and a therapeutic target for treating insulin resistance in type-2 diabetes patients. To confirm that 30-day treatment of RSG or a single low dose cranial irradiation did not alter baseline behavior in mice, we tested natural exploration and anxiety like behavior by exposing all groups to a novel context in open field test for 10 min. To determine if PPARγ agonism influences context discrimination via a neurogenesis-dependent manner with and without focal cranial irradiation, we tested our groups in a context fear discrimination memory task (Figure 3).

Results

Conclusion