The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer's Disease and Other Neurodegenerative Disorders

Abstract

Peroxisome proliferator activated receptor alpha (PPAR-α) belongs to the family of ligand-regulated nuclear receptors (PPARs). These receptors after heterodimerization with retinoid X receptor (RXR) bind in promotor of target genes to PPAR response elements (PPREs) and act as a potent transcription factors. PPAR-α and other receptors from this family, such as PPAR-β/δ and PPAR-γ are expressed in the brain and other organs and play a significant role in oxidative stress, energy homeostasis, mitochondrial fatty acids metabolism and inflammation. PPAR-α takes part in regulation of genes coding proteins that are involved in glutamate homeostasis and cholinergic/dopaminergic signaling in the brain. Moreover, PPAR-α regulates expression of genes coding enzymes engaged in amyloid precursor protein (APP) metabolism. It activates gene coding of α secretase, which is responsible for non-amyloidogenic pathway of APP degradation. It also down regulates β secretase (BACE-1), the main enzyme responsible for amyloid beta (Aβ) peptide release in Alzheimer Diseases (AD). In AD brain expression of genes of PPAR-α and PPAR-γ coactivator-1 alpha (PGC-1α) is significantly decreased. PPARs are altered not only in AD but in other neurodegenerative/neurodevelopmental and psychiatric disorder. PPAR-α downregulation may decrease anti-oxidative and anti-inflammatory processes and could be responsible for the alteration of fatty acid transport, lipid metabolism and disturbances of mitochondria function in the brain of AD patients. Specific activators of PPAR-α may be important for improvement of brain cells metabolism and cognitive function in neurodegenerative and neurodevelopmental disorders.

Keywords: App/aβ metabolism; Glutamatergic signaling; Mitochondria function; Neurodegeneration; Neuroprotection; PPAR-α.

Fig. 1

The role of PPAR-α in the brain (according to D’Orio et al. [136] with some modyfication)

Fig. 2

PPAR-α and it involvement in glutaminergic neurotrasmission and in glutamate homeostasis

Fig. 3

PPAR-α engagement in regulation of APP secretases in the brain

Fig. 4

Inhibition of PPAR-α in AD brain alters APP metabolism

Fig. 5

The role of PPAR-α, PPAR-γ and PGC1-α on mitochondria biogenesis and function. (according to Dominy and Puigserver [72]; Jornayvaz and Shulman [73]; Scrapulla et al. [6, 8])