Vol.:(0123456789) 1 3 Neurochemical Research https://doi.org/10.1007/s11064-020-02993-5 REVIEW The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer’s Disease and Other Neurodegenerative Disorders Sylwia Wójtowicz 1  · Anna K. Strosznajder 2  · Mieszko Jeżyna 2  · Joanna B. Strosznajder 1 Received: 8 December 2019 / Revised: 11 February 2020 / Accepted: 17 February 2020 © The Author(s) 2020 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 signifcant role in oxidative stress, energy homeostasis, mitochondrial fatty acids metabolism and infammation. PPAR-α takes part in regulation of genes coding pro- teins 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 signifcantly decreased. PPARs are altered not only in AD but in other neurodegenerative/neurodevelopmental and psychiatric disorder. PPAR-α downregula- tion may decrease anti-oxidative and anti-infammatory 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. Specifc activators of PPAR-α may be important for improvement of brain cells metabolism and cognitive function in neurodegenerative and neurodevelopmental disorders. Keywords PPAR-α · Glutamatergic signaling · App/aβ metabolism · Mitochondria function · Neurodegeneration · Neuroprotection Introduction Peroxisome proliferators activated receptors (PPARs) are family of ligand-regulated nuclear receptors that include PPAR-α, PPAR-β/δ and PPAR-γ. These receptors are encoded by distinct genes: PPAR-α (NR1C1), PPAR-β/δ (NUC1 or NR1C2) and PPAR-γ (NR1C3) located on chro- mosome 15, 17, and 6 in the mouse and on chromosome 22, 6, 3 in humans. The PPAR-γ gene alternative promotors are responsible for three isoforms (γ1, γ2, γ3) These PPARs genes encode proteins of 468, 441, 475 and 505 amino acids with 49–56 kDa [1, 2]. PPARs regulate transcriptions through a complex mecha- nism as described in review by Berger and Moller [3] and Nierenberg et al. [4]. The frst PPAR currently known as PPAR-α was discovered in 1990 [5]. PPARs after hetero- dimerization with RXR bind to the specifc promotor region of target genes described as PPAR response elements (PPREs) and act as transcription factor(s) [4]. PPARs coacti- vators, such as PPAR-γ coactivator-1 alpha (PGC1-α), exert signifcant role in transcription of genes through interaction not only with PPARs but also with other nuclear receptors as estrogen receptors (ERs) and nuclear respiratory factors 1 and 2 (NRF1, NRF2) [6]. These receptors play a signif- cant role in the regulation of transcription, energy and lipid metabolism and also in thermogenesis. PPAR-α regulates * Sylwia Wójtowicz swojtowicz@imdik.pan.pl * Joanna B. Strosznajder jstrosznajder@imdik.pan.pl 1 Department of Cellular Signaling, Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawińskiego st., 02-106 Warsaw, Poland 2 Faculty of Medicine, Medical University of Bialystok, 1 Kilinskiego st., 15-089 Białystok, Poland