Recent Insights on the Role of PPAR-β/δ in Neuroinflammation and Neurodegeneration, and Its Potential Target for Therapy

Abstract

Peroxisome proliferator-activated receptor (PPAR) β/δ belongs to the family of hormone and lipid-activated nuclear receptors, which are involved in metabolism of long-chain fatty acids, cholesterol, and sphingolipids. Similar to PPAR-α and PPAR-γ, PPAR-β/δ also acts as a transcription factor activated by dietary lipids and endogenous ligands, such as long-chain saturated and polyunsaturated fatty acids, and selected lipid metabolic products, such as eicosanoids, leukotrienes, lipoxins, and hydroxyeicosatetraenoic acids. Together with other PPARs, PPAR-β/δ displays transcriptional activity through interaction with retinoid X receptor (RXR). In general, PPARs have been shown to regulate cell differentiation, proliferation, and development and significantly modulate glucose, lipid metabolism, mitochondrial function, and biogenesis. PPAR-β/δ appears to play a special role in inflammatory processes and due to its proangiogenic and anti-/pro-carcinogenic properties, this receptor has been considered as a therapeutic target for treating metabolic syndrome, dyslipidemia, carcinogenesis, and diabetes. Until now, most studies were carried out in the peripheral organs, and despite of its presence in brain cells and in different brain regions, its role in neurodegeneration and neuroinflammation remains poorly understood. This review is intended to describe recent insights on the impact of PPAR-β/δ and its novel agonists on neuroinflammation and neurodegenerative disorders, including Alzheimer's and Parkinson's, Huntington's diseases, multiple sclerosis, stroke, and traumatic injury. An important goal is to obtain new insights to better understand the dietary and pharmacological regulations of PPAR-β/δ and to find promising therapeutic strategies that could mitigate these neurological disorders.

Keywords: Agonists; Alzheimer's disease; Hypoxia/ischemia; Lipid metabolism; Neurodegenerative disorders; Neuroprotection; PPAR delta.

Fig. 1

PPAR-β/δ expression in different brain parts and cells. PFC prefrontal cortex, NAC nucleus accumbens, AMY amygdala, VTA ventral tegmental area; ***, **, * level of PPAR-β/δ expression; on the basis of data described by Warden et al. (2016), Schnegg and Robbins (2011), Carnigila et al. (2013)

Fig. 2

The role of PPAR-β/δ in lipid metabolism. FA fatty acids, FAβO fatty acids-β oxidation, FATP fatty acids transport protein, FABP fatty acids binding protein, CPT1A carnitine palmitoyltransferase I, RXR retinoid X receptor, ATP adenosine triphosphate, TCA tricarboxylic acid, acetyl-CoA acetyl coenzyme A, LCFA long-chain fatty acids, CXCL1,2,10 chemokines 1,2,10, iNOS nitric oxide synthases (inducible form), TNF-α tumor necrosis factor α, IFNγ interferon gamma, IL1,6,10 interleukin 1,2,10, NFκB nuclear factor kappa-light-chain-enhancer of activated B cells

Fig. 3

PPAR-β/δ engagement in neurological disorders. AD-Alzheimer’s disease, PD Parkinson’s disease, HD Huntington’s disease, MS multiplex sclerosis, ALS amyotrophic lateral sclerosis

Fig. 4

Potential PPAR-β/δ mechanisms of action, constructive in Alzheimer’s disease