Changes in the activity of microglia, the primary immune cells of the central nervous system, are linked with major human diseases, including stroke, epilepsy, psychiatric disorders, and neurodegeneration. Cserép et al. identified a specialized morphofunctional communication site between microglial processes and neuronal cell bodies in the mouse and the human brain (see the Perspective by Nimmerjahn).
During adult hippocampal neurogenesis, most newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of intracellular contents. Here, we propose that phagocytosis is not merely passive corpse removal but has an active role in maintaining neurogenesis.
Hyperphosphorylation of the microtubule-associated protein tau and its resultant aggregation into neurofibrillary tangles (NFT) is a pathological characteristic of neurodegenerative disorders known as tauopathies. Tau is a neuronal protein involved in the stabilization of microtubule structures of the axon and the aberrant phosphorylation of tau is associated with several neurotoxic effects.
P2X7-targeting is emerging as promising therapeutic strategy for brain diseases. * P2X7 expression and function is altered during numerous brain diseases. * Regulation of P2X7 expression is complex ranging from genetic regulation to post-transcriptional alterations. * Different regulatory mechanisms may explain cell-specific P2X7 expression and function during pathology.
Nucleotides regulate the common molecular mechanisms that underlie neurodegenerative diseases; Therapeutic implications
Progression of neurodegenerative diseases is guided by common molecular mechanisms. * Extracellular nucleotides may regulate these common molecular mechanisms. * New therapeutic strategies might be based on enhancing or inhibiting these regulatory actions. Neurodegenerative diseases (ND) are a heterogeneous group of neurological disorders characterized by a progressive loss of neuronal function which results in neuronal death.
Astrocytic rather than neuronal P2X7 receptors modulate the function of the tri-synaptic network in the rodent hippocampus
Functional P2X7 receptors are missing at neurons of the mouse hippocampus. * Astrocytic/microglial P2X7 receptors are primary targets of ATP in mouse hippocampus. * Astrocytes and neurons cross-talk via astrocytic glutamate/GABA in mouse hippocampus.
ATP is released as a signaling molecule, or as a danger signal to the extracellular space in the brain. * P2X and P2Y receptors modulate microglia pro- or anti-inflammatory phenotypical shift. * Purinergic signaling dynamically control microglia physiological activity according to the context.
Amyloid Peptide Induced Neuroinflammation Increases the P2X7 Receptor Expression in Microglial Cells, Impacting on Its Functionality
Alzheimer disease is a neurodegenerative disease characterized by the presence of senile plaques composed of amyloid-β (Aβ) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have revealed that extracellular ATP, through its selective receptor P2X7 (P2X7R), is essential to neuroinflammation and neurotoxicity induced by Aβ.
* P2Rs involved in neuronal/neuroglial developmental processes. * P2Rs associated with schizophrenia, fetal alcohol and autism spectrum disorder. * Neuroinflammation and gut microflora underlying potential pathology of CNS.
The association between early neurological deterioration and whole blood purine concentration during acute stroke
Keywords: Stroke, Cerebrovascular disease, Deterioration, Purines, Penumbra Early neurological deterioration (END) describes worsening of symptoms during the initial period following stroke onset and is associated with poorer outcomes. Incidence ranges from 2.2 to 37.5% depending upon the choice of severity threshold and the time elapsed between assessments [ 1- 4].
Proteins and microRNAs are differentially expressed in tear fluid from patients with Alzheimer's disease
Aidan Kenny, 1 Eva M. Jiménez-Mateos, 2 María Ascensión Zea-Sevilla, 4 Alberto Rábano, 4 Pablo Gili-Manzanaro, 5 Jochen H. M. Prehn, 1, 6 David C. Henshall, 1, 6 Jesús Ávila, 3, 7 Tobias Engel, # 1, 6 and Félix Hernández # 3, 7 Alzheimer's disease (AD) is characterized by a progressive loss of neurons and cognitive functions.
Extracellular adenine nucleotides play important roles in cell-cell communication and tissue homeostasis. High concentrations of extracellular ATP released by dying cells are sensed as a danger signal by the P2X7 receptor, a non-specific cation channel. Studies in P2X7 knockout mice and numerous disease models have demonstrated an important role of this receptor in inflammatory processes.
Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by progressive loss of dopaminergic neurons that results in characteristic motor and non-motor symptoms. l-3,4 dihydroxyphenylalanine (l-DOPA) is the gold standard therapy for the treatment of PD. However, long-term use of l-DOPA leads to side effects such as dyskinesias and motor fluctuation.
Deletion of CRH From GABAergic Forebrain Neurons Promotes Stress Resilience and Dampens Stress-Induced Changes in Neuronal Activity
Dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in stress-related psychopathologies such as depression and anxiety. Although most studies have linked CRH/CRH receptor 1 signaling to aversive, stress-like behavior, recent work has revealed a crucial role for distinct CRH circuits in maintaining positive emotional valence and appetitive responses under baseline conditions.
Laura de Diego-García Álvaro Sebastián-Serrano Carolina Bianchi Caterina Di Lauro Miguel Díaz-Hernández Part of the Methods in Molecular Biology book series (MIMB, volume 2041) Imbalance in extracellular ATP levels in brain tissue has been suggested as a triggering factor for several neurological disorders.
Purine nucleoside use as surrogate markers of cerebral ischaemia during local and general anaesthetic carotid endarterectomy
In periods of cerebral ischaemia, adenosine triphosphate is metabolised, leading to accumulation of adenosine inosine and hypoxanthine. These can be measured in real time using peripheral blood samples intraoperatively. The primary aim of this study was to describe changes in purine concentrations in a cohort of patients undergoing carotid endarterectomy under general anaesthetic, and to evaluate correlation between changes in values with major perioperative steps.
Context-Specific Switch from Anti- to Pro-epileptogenic Function of the P2Y1 Receptor in Experimental Epilepsy
Extracellular ATP activates inflammatory responses to tissue injury. It is also implicated in establishing lasting network hyperexcitability in the brain by acting upon independent receptor systems. Whereas the fast-acting P2X channels have well-established roles driving neuroinflammation and increasing hyperexcitability, the slower-acting metabotropic P2Y receptors have received much less attention.
Maternal immune activation (MIA) is a principal environmental risk factor contributing to autism spectrum disorder (ASD), which compromises fetal brain development at critical periods of pregnancy and might be causally linked to ASD symptoms. We report that endogenous activation of the purinergic ion channel P2X7 (P2rx7) is necessary and sufficient to transduce MIA to autistic phenotype in male offspring.
Stroke is a leading cause of death and disability. Here, we examine whether point-of-care measurement of the purines, adenosine, inosine and hypoxanthine, which are downstream metabolites of ATP, has potential to assist the diagnosis of stroke. In a prospective ...
Epilepsy encompasses a heterogeneous group of neurological syndromes which are characterized by recurrent seizures affecting over 60 million people worldwide. Current anti-epileptic drugs (AEDs) are mainly designed to target ion channels and/or GABA or glutamate receptors.
The regulation of proteostasis in glial cells by nucleotide receptors is key in acute neuroinflammation | The FASEB Journal
The disturbances of cellular proteostasis caused by the alteration in the ubiquitin-proteasome system (UPS) have been proposed as a common mechanism underlying several neural pathologies that involve a neuroinflammatory process. As we have previously reported that the nucleotide receptor P2Y purinoceptor 2 (P2Y 2R) regulates the proteasomal catalytic activities, we wonder whether this receptor is involved in the UPS disturbances associated with the neuroinflammation process.
The adenosine receptor (AR) subtypes A 2A and A 2B are rhodopsin-like G s protein-coupled receptors whose expression is highly regulated under pathological, e.g. hypoxic, ischemic and inflammatory conditions. Both receptors play important roles in inflammatory and neurodegenerative diseases, are blocked by caffeine, and have now become major drug targets in immuno-oncology.
Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels
Hypophosphatasia (HPP) is a rare heritable metabolic bone disease caused by hypomorphic mutations in the ALPL (in human) or Akp2 (in mouse) gene, encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme. In addition to skeletal and dental malformations, severe forms of HPP are also characterized by the presence of spontaneous seizures.
MicroRNA-22 Controls Aberrant Neurogenesis and Changes in Neuronal Morphology After Status Epilepticus
Prolonged seizures (status epilepticus) may drive hippocampal dysfunction and epileptogenesis, at least partly, through an elevation in neurogenesis, dysregulation of migration and aberrant dendritic arborization of newly-formed neurons. MicroRNA-22 was recently found to protect against the development of epileptic foci, but the mechanisms remain incompletely understood.
Bi-directional genetic modulation of GSK-3β exacerbates hippocampal neuropathology in experimental status epilepticus
Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed throughout the brain and involved in vital molecular pathways such as cell survival and synaptic reorganization and has emerged as a potential drug target for brain diseases. A causal role for GSK-3, in particular the brain-enriched GSK-3β isoform, has been demonstrated in neurodegenerative diseases such as Alzheimer's and Huntington's, and in psychiatric diseases.
A novel BAC transgenic mouse model reveals glial restriction of P2X7 expression in the central and peripheral nervous systems.
Two subclasses of ligand-gated ion channels (ASIC3 and P2X3) are both present at sensory neurons and might be therefore subject to receptor crosstalk. Here authors use electrophysiology, biochemistry and co-immunoprecipitation to show that the two ion channels interact and affect P2X3 currents.
ATP released from astrocytes modulates action potential threshold and spontaneous excitatory postsynaptic currents in the neonatal rat prefrontal cortex
Regulation of Hippocampal 5-HT Release by P2X7 Receptors in Response to Optogenetic Stimulation of Median Raphe Terminals of Mice
Serotonergic and glutamatergic neurons of median raphe region (MRR) play a pivotal role in the modulation of affective and cognitive functions. These neurons synapse both onto themselves and remote cortical areas. P2X7 receptors ( P2rx7) are ligand gated ion channels expressed by central presynaptic excitatory nerve terminals and involved in the regulation of neurotransmitter release.
Major depressive disorder is characterized by structural and functional abnormalities of cortical and limbic brain areas, including a decrease in spine synapse number in the dentate gyrus of the hippocampus. Recent studies highlighted that both genetic and pharmacological invalidation of the purinergic P2X7 receptor (P2rx7) leads to antidepressant-like phenotype in animal experiments; however, the impact of P2rx7 on depression-related structural changes in the hippocampus is not clarified yet.
Heterozygosity for the Mood Disorder-Associated Variant Gln460Arg Alters P2X7 Receptor Function and Sleep Quality
A single nucleotide polymorphism substitution from glutamine (Gln, Q) to arginine (Arg, R) at codon 460 of the purinergic P2X7 receptor (P2X7R) has repeatedly been associated with mood disorders. The P2X7R-Gln460Arg variant per se is not compromised in its function. However, heterologous expression of P2X7R-Gln460Arg together with wild-type P2X7R has recently been demonstrated to impair receptor function.
Modulation of P2X7 purinergic receptor activity by extracellular Zn2+ in cultured mouse hippocampal astroglia
The P2X7R protein, a P2 type purinergic receptor functioning as a non-selective cation channel, is expressed in different cell types of the central ne...