ADP microglia

Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas. The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated. In this observational study, we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases (LBDs) and Alzheimer disease (AD), shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration...

Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-β peptide (Aβ) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection; however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology...

BACKGROUND: Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive degeneration of photoreceptor cells. Ocular redox status is altered in RP suggesting oxidative stress could contribute to their progression. In this study, we investigated the effect of a mixture of nutraceuticals with antioxidant properties (NUT) on retinal degeneration in rd10 mice, a model of RP. METHODS: NUT was orally administered to rd10 mice from postnatal day (PD) 9 to PD18...

The poly(ADP-ribose) polymerase inhibitor PJ34 has recently been reported to increase cerebral blood flow, via the endothelial NO synthase, in the naive mouse brain throughout life. We addressed here the benefits of PJ34 after neonatal ischemia on hemodynamics and components of the neurovascular unit including the blood-brain barrier (BBB), microglia, and astrocytes. Nine-day-old mice were subjected to permanent MCA occlusion (pMCAo), and treated with either PBS or PJ34 (10 mg/kg). Mean blood-flow velocities (mBFV) were measured in both internal carotid arteries (ICA) and basilar trunk (BT) using Doppler-ultrasonography...

Microglia, the immune cells of the central nervous system, play critical roles in brain physiology and pathology. We report a novel approach that produces, within 10 days, the differentiation of human induced pluripotent stem cells (hiPSCs) into microglia (iMG) by forced expression of both SPI1 and CEBPA. High-level expression of the main microglial markers and the purity of the iMG cells were confirmed by RT-qPCR, immunostaining, and flow cytometry analyses. Whole-transcriptome analysis demonstrated that these iMGs resemble human fetal/adult microglia but not human monocytes...

Lysophosphatidic acid (LPA) species are a family of bioactive lipids that transmit signals via six cognate G protein-coupled receptors, which are required for brain development and function of the nervous system. LPA affects the function of all cell types in the brain and can display beneficial or detrimental effects on microglia function. During earlier studies we reported that LPA treatment of microglia induces polarization towards a neurotoxic phenotype. In the present study we investigated whether these alterations are accompanied by the induction of a specific immunometabolic phenotype in LPA-treated BV-2 microglia...

Stroke is a major public health problem leading to high rates of death and disability worldwide, but no effective pharmacological therapy is currently available except for the use of PLAT (plasminogen activator, tissue). Here we show that PARP14 (poly (ADP-ribose) polymerase family, member 14) level was significantly increased in the peri-infarct zone of photothrombotic stroke (PT) mice. Genetic knockdown and pharmacological inhibition of PARP14 aggravated functional impairment and increased infarct volume in PT mice, while overexpression of PARP14 displayed the opposite effects...

Microglial cells are the primary immune cell resident in the brain. Growing evidence indicates that microglial cells play a prominent role in alcohol-induced brain pathologies. However, alcohol-induced effects on microglial cells and the underlying mechanisms are not fully understood, and evidence exists to support generation of oxidative stress due to NADPH oxidases (NOX_-mediated production of reactive oxygen species (ROS). Here, we investigated the role of the oxidative stress-sensitive Ca2+ -permeable transient receptor potential melastatin-related 2 (TRPM2) channel in ethanol (EtOH)-induced microglial cell death using BV2 microglial cells...

Microglia cells are versatile players coordinating inflammatory and regenerative processes in the central nervous system in which sphingosine-1-phosphate (S1P)-mediated migration is essential. We investigated the involved signaling cascade by means of voltage clamp, measurement of ATP secretion, and wound healing assay in murine microglial BV-2 cells. S1P and extracellular hypoosmolar solution evoked an anion conductance of the cell membrane. The corresponding ion currents were inhibited by intracellular hypoosmolar solution and by the anion channel antagonists NPPB, tamoxifen, and carbenoxolone, pointing to the activation of volume-regulated anion channels (VRAC)...

Moesin is a member of the ezrin, radixin and moesin (ERM) proteins that are involved in the formation and/or maintenance of cortical actin organization through their cross-linking activity between actin filaments and proteins located on the plasma membranes as well as through regulation of small GTPase activities. Microglia, immune cells in the central nervous system, show dynamic reorganization of the actin cytoskeleton in their process elongation and retraction as well as phagocytosis and migration. In microglia, moesin is the predominant ERM protein...

Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1 . Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes...

Alzheimer's disease (AD) is a neurodegenerative disease mainly associated with aging, oxidative stress and genetic mutations. There are two pathological proteins involved in AD; Amyloid-β peptide and microtubule-associated protein Tau (MAPT). The β- and γ-secretase enzyme cleaves the Amyloid precursor protein, which results in the formation of extracellular plaques in brain. While, Tau undergoes hyperphosphorylation and other post-translational modifications (PTMs), which eventually generates Tau oligomers, and intracellular neurofibrillary tangles (NFTs) in neurons...

We found interactions between dopamine and oxidative damage in the striatum involved in advanced neurodegeneration, which probably change the microglial phenotype. We observed possible microglia dystrophy in the striatum of neurodegenerative brains. To investigate the interactions between oxidative damage and microglial phenotype, we quantified myeloperoxidase (MPO), poly (ADP-Ribose) (PAR), and triggering receptors expressed on myeloid cell 2 (TREM2) using enzyme-linked immunosorbent assay (ELISA). To test the correlations of microglia dystrophy and tauopathy, we quantified translocator protein (TSPO) and tau fibrils using autoradiography...

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by the progressive and irreversible loss of vision. We previously found that intraperitoneal administration of Adalimumab, a monoclonal anti-TNFα antibody, slowed down retinal degeneration in the murine model of RP, the rd10 mice. The aims of this study were to improve its neuroprotective effect and to deepen understanding of the molecular mechanisms involved in this effect. We analyzed (i) the in vitro effect of Adalimumab on the TNFα-mediated cell death in retinal cells; (ii) the effect of a single intravitreal injection of Adalimumab on retinal degeneration in rd10 mice at postnatal day (P) 23...

PURPOSE: Intracranial hemorrhage (ICH) is a devastating disease with high mortality and morbidity. After ICH, iron released from the hematoma plays a crucial role in secondary brain injury. Deferasirox (DFR) is a trivalent iron chelator, which was approved to treat iron overload syndrome after transfusion. The aim of the present study was to investigate the protective effects of DFR in both in vitro and in vivo ICH models. METHODS: Using a hemin-induced SH-SY5Y cell damage model, we performed an intracellular bivalent iron (Fe2+ ) accumulation assay, cell death assay, oxidative stress assessments, and Western blotting analysis...

IQSEC3, a guanine nucleotide exchange factor for ADP-ribosylation factors (ARF-GEFs) is specifically expressed at GABAergic synapses, and its loss increases seizure susceptibility in mice. However, the contribution of microglia to initiation and/or progression of seizures in IQSEC3-deficient mice has not been investigated. In the current study, we show that mice with hippocampal dentate gyrus (DG)-specific IQSEC3 knockdown (KD) exhibit microglial activation and death of DG granule cell. Furthermore, treatment of IQSEC3-KD mice with minocycline, an inhibitor of microglial activation, blocks DG granule neuron cell death and the occurrence of spontaneous seizures without affecting GABAergic synapse deficits or loss of somatostatin...

OBJECTIVE: The present study determines whether Cav-1 modulates the initiation, development and maintenance of type-2 DNP via the Rac1/NOX2-NR2B signaling pathway. METHODS: After regular feeding for three days, these rats were randomly divided into two groups: control group with normal-diet (maintenance feed) ( n =8); type-2 DM group ( n =8). In the type-2 DM group, the rats were fed with a high-fat and high-sugar diet, and received a single intraperitoneal streptozotocin (STZ) injection (35 mg/kg)...

Microglial cells, the resident macrophages of the central nervous system (CNS), exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell-damaging factors, they get transformed into an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species, and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia have a number of important physiological functions in the CNS; for example, they shield small disruptions of the blood-brain barrier by their processes, dynamically interact with synaptic structures, and clear surplus synapses during development...

Quinolinate (Quin) is a classic example of a biochemical double-edged sword, acting as both essential metabolite and potent neurotoxin. Quin is an important metabolite in the kynurenine pathway of tryptophan catabolism leading to the de novo synthesis of nicotinamide adenine dinucleotide (NAD+ ). As a precursor for NAD+ , Quin can direct a portion of tryptophan catabolism toward replenishing cellular NAD+ levels in response to inflammation and infection. Intracellular Quin levels increase dramatically in response to immune stimulation [e...

Chronic neuroinflammation driven by microglia is a characteristic feature associated with numerous neurodegenerative diseases. While acute inflammation can assist with recovery and repair, prolonged microglial pro-inflammatory responses are known to exacerbate neurodegenerative processes. Yet, detrimental outcomes of extended microglial activation are counterbalanced by beneficial outcomes including phagocytosis and release of trophic factors promoting neuronal viability. Our past work has shown that the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is a key signaling hub driving pro-inflammatory microglia responses, but the signaling pathway maintaining PARP-1 activation remains elusive...