Current View on PPAR-α and Its Relation to Neurosteroids in Alzheimer's Disease and Other Neuropsychiatric Disorders: Promising Targets in a Therapeutic Strategy.

Peroxisome proliferator-activated receptors (PPARs) may play an important role in the pathomechanism/pathogenesis of Alzheimer's disease (AD) and several other neurological/neuropsychiatric disorders. AD leads to progressive alterations in the redox state, ion homeostasis, lipids, and protein metabolism. Significant alterations in molecular processes and the functioning of several signaling pathways result in the degeneration and death of synapses and neuronal cells, leading to the most severe dementia. Peroxisome proliferator-activated receptor alpha (PPAR-α) is among the processes affected by AD; it regulates the transcription of genes related to the metabolism of cholesterol, fatty acids, other lipids and neurotransmission, mitochondria biogenesis, and function. PPAR-α is involved in the cholesterol transport to mitochondria, the substrate for neurosteroid biosynthesis. PPAR-α-coding enzymes, such as sulfotransferases, which are responsible for neurosteroid sulfation. The relation between PPAR-α and cholesterol/neurosteroids may have a significant impact on the course and progression of neurodegeneration/neuroprotection processes. Unfortunately, despite many years of intensive studies, the pathogenesis of AD is unknown and therapy for AD and other neurodegenerative diseases is symptomatic, presenting a significant goal and challenge today. This review presents recent achievements in therapeutic approaches for AD, which are targeting PPAR-α and its relation to cholesterol and neurosteroids in AD and neuropsychiatric disorders.

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

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-ß/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 ß secretase (BACE-1), the main enzyme responsible for amyloid beta (Aß) 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.

The role of synthetic ligand of PPARα in regulation of transcription of genes related to mitochondria biogenesis and dynamic in an animal model of Alzheimer's disease.

Peroxisome proliferator-activated receptors α (PPARα) are members of the nuclear receptors family and a very potent transcription factor engaged in the regulation of lipid and energy metabolism. Recent data suggest that PPARα could play an important role in the pathomechanism of Alzheimer's disease (AD) and other neuropsychiatric disorders. This study focused on the effect of a synthetic ligand of PPARα, GW7647 on the transcription of genes encoding proteins of mitochondria biogenesis and dynamics in the brain of AD mice. The experiments were carried out using 12-month-old female FVB-Tg mice with the V717I mutation of amyloid precursor protein (APP + ) and mice without the transgene (APP - ). Moreover, APP + and APP - mice were treated for 14 days with GW7647 administered subcutaneously with a dose 5 mg/kg b.w. Brain cortex was used and qRT-PCR was performed. Our data indicated that GW7647 upregulated the expression of genes encoding proteins of mitochondria biogenesis in ADTg mice. GW7647 enhanced the level of mRNA of Ppargc1, Nrf2 and Tfam in APP + as compared to APP - mice treated with GW7647. Moreover, our studies demonstrated that GW7647 had no effect on genes that regulate mitochondria fission and fusion of ADTg mice as correlated to mice without the transgene. Our results indicate that the ligand of PPARα, GW7647 may exert a promising neuroprotective effect through the regulation of transcription of genes coding proteins of mitochondria biogenesis. These data suggest that activation of PPARα at an early stage of AD could be a helpful strategy for slowing the progression of neurodegeneration.

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

Peroxisome proliferator-activated receptor (PPAR) ß/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-ß/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-ß/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-ß/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-ß/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-ß/δ and to find promising therapeutic strategies that could mitigate these neurological disorders.