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

摘要

Peroxisome proliferator activated receptor alpha (PPAR-alpha) 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-alpha and other receptors from this family, such as PPAR-beta/delta and PPAR-gamma 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-alpha takes part in regulation of genes coding proteins that are involved in glutamate homeostasis and cholinergic/dopaminergic signaling in the brain. Moreover, PPAR-alpha regulates expression of genes coding enzymes engaged in amyloid precursor protein (APP) metabolism. It activates gene coding of alpha secretase, which is responsible for non-amyloidogenic pathway of APP degradation. It also down regulates beta secretase (BACE-1), the main enzyme responsible for amyloid beta (A beta) peptide release in Alzheimer Diseases (AD). In AD brain expression of genes of PPAR-alpha and PPAR-gamma coactivator-1 alpha (PGC-1 alpha) is significantly decreased. PPARs are altered not only in AD but in other neurodegenerative/neurodevelopmental and psychiatric disorder. PPAR-alpha 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-alpha may be important for improvement of brain cells metabolism and cognitive function in neurodegenerative and neurodevelopmental disorders.