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MicroRNAs (miRNAs) are small, highly conserved non‐coding RNA molecules that post‐transcriptionally regulate protein expression and most biological processes. Mature miRNAs are recruited to the RNA‐induced silencing complex (RISC) and target mRNAs via complementary base‐pairing, thus resulting in translational inhibition and/or transcript degradation. Here, we present evidence implicating miRNAs within...
Na+/H+ exchanger (NHE1) activation is required for multiple microglial functions. We investigated effects of selective deletion of microglial Nhe1 in Cx3cr1‐CreER;Nhe1f/f mice on neuroinflammation and tissue repair after ischemic stroke. Infarct volume was similar in corn oil or tamoxifen (Tam)‐treated mice at 48 hr and 14 days post‐stroke. However, the Tam‐treated mice showed significantly higher...
Intercellular communication via gap junction channels between oligodendrocytes and between astrocytes as well as between these cell types is essential to maintain the integrity of myelin in the central nervous system. Oligodendrocyte gap junction connexin‐47 (Cx47) is a key element in this crosstalk and indeed, mutations in human Cx47 cause severe myelin disorders. However, the permeation properties...
Neurogenesis is sustained throughout life in the mammalian brain, supporting hippocampus‐dependent learning and memory. Its permanent alteration by status epilepticus (SE) is associated with learning and cognitive impairments. The mechanisms underlying the initiation of altered neurogenesis after SE are not understood. Glial fibrillary acidic protein‐positive radial glia (RG)‐like cells proliferate...
Neuroinflammatory diseases such as multiple sclerosis are characterized by infiltration of lymphocytes into the central nervous system followed by demyelination and axonal degeneration. While evidence suggests that activated T lymphocytes induce neurotoxicity and impair function of neural stem cells, the effect of T cells on oligodendrocyte progenitor cells (OPCs) is still uncertain, partly due to...
Astrocyte‐derived ciliary neurotrophic factor (CNTF) promotes adult subventricular zone (SVZ) neurogenesis. We found that focal adhesion kinase (FAK) and JNK, but not ERK or P38, repress CNTF in vitro. Here, we defined the FAK–JNK pathway and its regulation of CNTF in mice, and the related leukemia inhibitory factor (LIF) and interleukin‐6 (IL‐6), which promote stem cell renewal at the expense of...
The transition of differentiated Schwann cells to support of nerve repair after injury is accompanied by remodeling of the Schwann cell epigenome. The EED‐containing polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 methylation and represses key nerve repair genes such as Shh, Gdnf, and Bdnf, and their activation is accompanied by loss of H3K27 methylation. Analysis of nerve injury in mice...
Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the...
Discovery of neuroprotective pathways is one of the major priorities for neuroscience. Astrocytes are natural neuroprotectors and it is likely that brain resilience can be enhanced by mobilizing their protective potential. Among G‐protein coupled receptors expressed by astrocytes, two highly related receptors, GPR37L1 and GPR37, are of particular interest. Previous studies suggested that these receptors...
Microglia are known to regulate several aspects of the development of the central nervous system. When microglia colonize the spinal cord, from E11.5 in the mouse embryo, they interact with growing central axons of dorsal root ganglion sensory neurons (SNs), which suggests that they may have some functions in SN development. To address this issue, we analyzed the effects of embryonic macrophage ablation...
Loss of substantia nigra dopaminergic neurons results in Parkinson disease (PD). Degenerative PD usually presents in the seventh decade whereas genetic disorders, including mutations in PARK2, predispose to early onset PD. PARK2 encodes the parkin E3 ubiquitin ligase which confers pleotropic effects on mitochondrial and cellular fidelity and as a mediator of endoplasmic reticulum (ER) stress signaling...
Oligodendrocytes myelinate neuronal axons to increase conduction velocity in the vertebrate central nervous system (CNS). Recent studies revealed that myelin formed on highly active axons is more stable compared to activity‐silenced axons, and length of the myelin sheath is longer in active axons as well in the zebrafish larva. However, it is unclear whether oligodendrocytes preferentially myelinate...
When activated, microglial cells have the potential not only to secrete typical proinflammatory mediators but also to release the neurotransmitter glutamate in amounts that may promote excitotoxicity. Here, we wished to determine the potential of the Parkinson's disease (PD) protein α‐Synuclein (αS) to stimulate glutamate release using cultures of purified microglial cells. We established that glutamate...
Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is,...
Oxidative stress and oxidative DNA damage are early features of mild cognitive impairment and Alzheimer's disease (AD), occurring before the formation of classical AD neuropathology, and resulting from an imbalance between pro‐ and anti‐oxidants. Astrocytes play a major neuroprotective role, producing high levels of anti‐oxidants including metallothionein‐I and ‐II (MT‐I/II). In the present study...
Neuroprotective effects of erythropoietin (EPO) on peripheral nerve injury remain uncertain. This study investigated the efficacy of EPO in attenuating median nerve chronic constriction injury (CCI)‐induced neuropathy. Animals received an intraneural injection of EPO at doses of 1,000, 3,000, or 5,000 units/kg 15 min before median nerve CCI. Afterwards, the behavioral and electrophysiological tests...
Microglia are the resident immune cell of the central nervous system (CNS), and serve to protect and maintain the local brain environment. Microglia are critically dependent on signaling through the colony‐stimulating factor 1 receptor (CSF1R); administration of CSF1R inhibitors that cross the blood brain barrier (BBB) lead to the elimination of up to 99% of microglia, depending on CNS exposure and...
To study the role of L‐type voltage‐gated Ca++ channels in oligodendrocyte development, we used a mouse model of Timothy syndrome (TS) in which a gain‐of‐function mutation in the α1 subunit of the L‐type Ca++ channel Cav1.2 gives rise to an autism spectrum disorder (ASD). Oligodendrocyte progenitor cells (OPCs) isolated from the cortex of TS mice showed greater L‐type Ca++ influx and displayed characteristics...
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