Peroxisomal Proliferator-Activated Receptor β/δ Deficiency Induces Cognitive Alterations

Abstract

BackgroundPPARβ/δ, the most PPAR abundant isotype in the central nervous system is involved in the modulation of microglial homeostasis and metabolism. Several studies have demonstrated that people suffering from type 2 diabetes mellitus develop cognitive decline turning insulin resistance one of the best predictors of this disturbance. Although numerous investigations have studied the role of PPARb/d in metabolism, its role in neuronal and cognitive function has been underexplored. Therefore, the aim of the study is to determine the role of PPARb/d in the neuropathological pathways involved in the development of cognitive decline and as to whether a risk factor involved in cognitive loss such as obesity modulates neuropathological markers.6-month-old male PPARβ/δ-null (PPARβ/δ-/-) and wildtype (WT) littermates with the same genetic background (C57BL/6X129/SV) and exceptionally, C57BL/6 were used. After the weaning, animals were fed either with conventional chow (CT) or with a palmitic acid-enriched diet containing 45% of fat mainly from hydrogenated coconut oil (HFD). Thus, four groups were defined: WT CT, WT HFD, PPARβ/δ-/- CT and PPARβ/δ-/- HFD and several pathological mechanisms involved in cognitive decline were analyzed.ResultsOur results confirmed that C57BL/6X129/SV showed significantly increased levels of anxiety compared to C57BL/6. Therefore, to evaluate cognitive decline, behavioral tests were dismissed, and dendritic spine quantification and other biochemical biomarkers were performed.PPARβ/δ-/- mice exhibited a decrease in dendritic spine density and synaptic markers, suggesting an alteration in cognitive function and synaptic plasticity. Likewise, our study demonstrated that the lack of PPARβ/δ receptor enhances gliosis in the hippocampus, contributing to astrocyte and microglial activation and also induced an increase in neuroinflammatory biomarkers. Additionally, alterations in the hippocampal insulin receptor pathway were found. Interestingly, while some of the disturbances caused by the lack of PPARβ/δ were not affected by feeding the HFD, others were exacerbated or required the combination of both factors.ConclusionsTaken together, these findings suggest that the loss of PPARβ/δ-/- affects neuronal and synaptic structure, contributing to cognitive dysfunction and, they also present this receptor as a possible new target for the treatment of cognitive decline.