Alterations in mRNA level of proteins related to redox state and mitochondria in an Alzheimer's disease animal model: Promising targets in neuroprotection.

Oxidative stress and disturbances of mitochondrial function in the brain play a crucial role in Alzheimer's disease (AD). However, little is known about the dynamics of these changes in different parts of the brain at the early stage of AD. This study aimed to determine the expression of genes encoding superoxide dismutases (SOD1, SOD2), poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs).

Inhibitor of bromodomain and extraterminal domain proteins decreases transcription of Cd33 in the brain of mice subjected to systemic inflammation; a promising strategy for neuroprotection.

The neuroinflammation is a crucial component of virtually all neurodegenerative disorders, including Alzheimer's disease (AD). The bacterial lipopolysaccharide (LPS), a potent activator of the innate immune system, was suggested to influence or even trigger the neuropathological alterations in AD. LPS-induced neuroinflammation involves changes in transcription of several genes, thus controlling these molecular processes may be a potentially efficient strategy to attenuate the progression of AD.

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.

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.

Down-regulation of cyclin D2 in amyloid β toxicity, inflammation, and Alzheimer's disease.

In the current study, we analyzed the effects of the systemic inflammatory response (SIR) and amyloid β (Aβ) peptide on the expression of genes encoding cyclins and cyclin-dependent kinase (Cdk) in: (i) PC12 cells overexpressing human beta amyloid precursor protein (βAPP), wild-type (APPwt-PC12), or carrying the Swedish mutantion (APPsw-PC12); (ii) the murine hippocampus during SIR; and (iii) Alzheimer's disease (AD) brain. In APPwt-PC12 expression of cyclin D2 (cD2) was exclusively reduced, and in APPsw-PC12 cyclins cD2 and also cA1 were down-regulated, but cA2, cB1, cB2, and cE1 were up-regulated. In the SIR cD2, cB2, cE1 were found to be significantly down-regulated and cD3, Cdk5, and Cdk7 were significantly up-regulated.

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer's Disease.

The physiological balance between excitation and inhibition in the brain is significantly affected in Alzheimer's disease (AD). Several neuroactive compounds and their signaling pathways through various types of receptors are crucial in brain homeostasis, among them glutamate and γ-aminobutyric acid (GABA). Activation of microglial receptors regulates the immunological response of these cells, which in AD could be neuroprotective or neurotoxic.

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson's Disease.

Molecular studies have provided increasing evidence that Parkinson's disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function-e.

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

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).

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders.

Acute systemic inflammatory response (SIR) triggers an alteration in the transcription of brain genes related to neuroinflammation, oxidative stress and cells death. These changes are also characteristic for Alzheimer's disease (AD) neuropathology. Our aim was to evaluate gene expression patterns in the mouse hippocampus (MH) by using microarray technology 12 and 96 h after SIR evoked by lipopolysaccharide (LPS).

Fingolimod Affects Transcription of Genes Encoding Enzymes of Ceramide Metabolism in Animal Model of Alzheimer's Disease.

The imbalance in sphingolipid signaling may be critically linked to the upstream events in the neurodegenerative cascade of Alzheimer's disease (AD). We analyzed the influence of mutant (V717I) amyloid β precursor protein (AβPP) transgene on sphingolipid metabolism enzymes in mouse hippocampus. At 3 months of age AβPP/Aβ presence upregulated enzymes of ceramide turnover on the salvage pathway: ceramide synthases (CERS2, CERS4, CERS6) and also ceramidase ACER3.

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-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.

Alterations of Transcription of Genes Coding Anti-oxidative and Mitochondria-Related Proteins in Amyloid β Toxicity: Relevance to Alzheimer's Disease.

A growing body of evidence indicates that pathological forms of amyloid beta (Aβ) peptide contribute to neuronal degeneration and synaptic loss in Alzheimer's disease (AD). In this study, we investigated the impact of exogenous Aβ oligomers (AβO) and endogenously liberated Aβ peptides on transcription of genes for anti-oxidative and mitochondria-related proteins in cell lines (neuronal SH-SY5Y and microglial BV2) and in brain cortex of transgenic AD (Tg-AD) mice, respectively. Our results demonstrated significant AβO-evoked changes in transcription of genes in SH-SY5Y cells, where AβO enhanced expression of Sod1, Cat, mt-Nd1, Bcl2, and attenuated Sirt5, Sod2 and Sdha.

Sphingosine kinase 1/sphingosine-1-phosphate receptors dependent signalling in neurodegenerative diseases. The promising target for neuroprotection in Parkinson's disease.

Parkinson's disease (PD) is one of the most common serious neurodegenerative disorders in the world. The incidence of PD appears to be growing and this illness has an unknown pathogenesis. PD is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra (SN), with an enigmatic cause in most individuals.

Pramipexole and Fingolimod exert neuroprotection in a mouse model of Parkinson's disease by activation of sphingosine kinase 1 and Akt kinase.

Parkinson's disease (PD) is one of the most severe neurodegenerative diseases with unknown pathogenesis and currently unsuccessful therapies. Recently, neuroprotection via sphingosine-1-phosphate (S1P)-dependent signalling has become a promising target for the treatment of neurodegenerative disorders. Our previous study demonstrated down-regulation and inhibition of the S1P-synthesizing enzyme sphingosine kinase 1 (SPHK1) in a PD cellular model.

Inhibition of poly(ADP-ribose) polymerase-1 alters expression of mitochondria-related genes in PC12 cells: relevance to mitochondrial homeostasis in neurodegenerative disorders.

Alzheimer's disease (AD) is characterized by the release of amyloid beta peptides (Aβ) in the form of monomers/oligomers which may lead to oxidative stress, mitochondria dysfunction, synaptic loss, neuroinflammation and, in consequence, to overactivation of poly(ADP-ribose) polymerase-1 (PARP-1). However, Aβ peptides are also released in the brain ischemia, traumatic injury and in inflammatory response. PARP-1 is suggested to be a promising target in therapy of neurodegenerative disorders.

Inhibition of Poly(ADP-ribose) Polymerase-1 Enhances Gene Expression of Selected Sirtuins and APP Cleaving Enzymes in Amyloid Beta Cytotoxicity.

Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer's disease (AD). Our previous results indicated that amyloid beta (Aβ) peptides and inflammation led to activation of PARP1 and cell death.

Alzheimer's amyloid-β peptide disturbs P2X7 receptor-mediated circadian oscillations of intracellular calcium.

Recent data indicate that Alzheimer's disease (AD) is associated with disturbances of the circadian rhythm in patients. We examined the effect of amyloid-β (Aβ) peptide, the main component of the senile plaques playing a critical role in the deregulation of calcium (Ca) homeostasis in AD, on the circadian oscillation of cytosolic calcium (Ca) levels . The experiments we carried out in human primary skin fibroblasts.

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders.

Sirtuins (SIRT1-SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD levels and thus on the cellular metabolic status. SIRTs regulate energy metabolism and mitochondrial function. They orchestrate the stress response and damage repair.

The mechanisms regulating cyclin-dependent kinase 5 in hippocampus during systemic inflammatory response: The effect on inflammatory gene expression.

Cyclin-dependent kinase 5 (Cdk5) is critical for nervous system's development and function, and its aberrant activation contributes to pathomechanism of Alzheimer's disease and other neurodegenerative disorders. It was recently suggested that Cdk5 may participate in regulation of inflammatory signalling. The aim of this study was to analyse the mechanisms involved in regulating Cdk5 activity in the brain during systemic inflammatory response (SIR) as well as the involvement of Cdk5 in controlling the expression of inflammatory genes.

The Lipoxygenases: Their Regulation and Implication in Alzheimer's Disease.

Inflammatory processes and alterations of lipid metabolism play a crucial role in Alzheimer's disease (AD) and other neurodegenerative disorders. Polyunsaturated fatty acids (PUFA) metabolism impaired by cyclooxygenases (COX-1, COX-2), which are responsible for formation of several eicosanoids, and by lipoxygenases (LOXs) that catalyze the addition of oxygen to linolenic, arachidonic (AA), and docosahexaenoic acids (DHA) and other PUFA leading to formation of bioactive lipids, significantly affects the course of neurodegenerative diseases. Among several isoforms, 5-LOX and 12/15-LOX are especially important in neuroinflammation/neurodegeneration.

The Molecular Mechanism of Amyloid β42 Peptide Toxicity: The Role of Sphingosine Kinase-1 and Mitochondrial Sirtuins.

Our study focused on the relationship between amyloid β 1-42 (Aβ), sphingosine kinases (SphKs) and mitochondrial sirtuins in regulating cell fate. SphK1 is a key enzyme involved in maintaining sphingolipid rheostat in the brain. Deregulation of the sphingolipid metabolism may play a crucial role in the pathogenesis of Alzheimer's disease (AD).

The key role of sphingosine kinases in the molecular mechanism of neuronal cell survival and death in an experimental model of Parkinson's disease.

Sphingosine kinases (Sphk1/2 EC 2.7.1.

Baclofen or nNOS inhibitor affect molecular and behavioral alterations evoked by traumatic spinal cord injury in rat spinal cord.

Background Context: The loss of descending control after spinal cord injury (SCI) and incessant stimulation of Ia monosynaptic pathway, carrying proprioceptive impulses from the muscles and tendons into the spinal cord, evoke exaggerated α-motoneuron activity leading to increased reflex response. Previous results from our laboratory have shown that Ia monosynaptic pathway is nitrergic.

Purpose: The aim of this study was to find out whether nitric oxide produced by neuronal nitric oxide synthase (nNOS) plays a role in setting the excitability of α-motoneurons after thoracic spinal cord transection.

Sphingosine-1-phosphate and its effect on glucose deprivation/glucose reload stress: from gene expression to neuronal survival.

Sphingosine kinase-1 (Sphk1-1, EC 2.7.1.

Sphingosine kinases/sphingosine-1-phosphate and death Signalling in APP-transfected cells.

It has been postulated that disturbances in the sphingolipid metabolism play a key role in the pathogenesis of Alzheimer's disease (AD). An alteration in sphingosine kinases 1, 2 (SphK1/2) and sphingosine-1-phosphate (S1P) was recently reported in AD. However, the effect of AD-related amyloid beta (Aβ) peptides on SphK1/2 and the role of S1P in Aβ toxicity have not been fully elucidated.