Adult neurogenesis is regulated by a number of cellular players within the neurogenic niche. Astrocytes participate actively in brain development, regulation mature central nervous system (CNS), and plasticity. They are important regulators local environment adult niches through secretion diffusible morphogenic factors, such as Wnts. control niche also membrane-associated however, identity these factors mechanisms involved largely unknown. In this study, we sought to determine underlying our...

Abstract We tested the hypothesis that astrocytes grown in a suitable three‐dimensional (3D) cell culture system exhibit morphological and biochemical features of vivo are otherwise lost upon transfer from to two‐dimensional (2D) environment. First, we report development novel bioactively coated nanofiber‐based 3D (Bioactive3D) supports cultures primary mouse astrocytes. Second, show Bioactive3D maintains ‐like complexity cultured cells, allows movement astrocyte filopodia way resembles...

Abstract Oxidative stress is one of the earliest events in Alzheimer’s disease (AD). A chemical genetic screen revealed that deregulated cyclin‐dependent kinase 5 (Cdk5) may cause oxidative by compromising cellular anti‐oxidant defense system. Using novel Cdk5 modulators, we show mechanism which can induce disease’s early stage and cell death late stage. dysregulation upon neurotoxic insults results reactive oxygen species (ROS) accumulation neuronal cells because inactivation peroxiredoxin...

Abstract Background In immune-mediated diseases of the central nervous system, astrocytes exposed to interferon-γ (IFN-γ) can express major histocompatibility complex (MHC) class II molecules and antigens on their surface. MHC are thought be delivered cell surface by membrane-bound vesicles. However, characteristics dynamics this vesicular traffic unclear, particularly in reactive astrocytes, which overexpress intermediate filament (IF) proteins that may affect trafficking. The aim study was...

Abstract Intermediate filaments (also termed nanofilaments) are involved in many cellular functions and play important roles responses to stress. The upregulation of glial fibrillary acidic protein (GFAP) vimentin (Vim), intermediate filament proteins astrocytes, is the hallmark astrocyte activation reactive gliosis response injury, ischemia or neurodegeneration. Reactive essential for protective role astrocytes at acute stages neurotrauma ischemic stroke. However, GFAP Vim were also linked...

Golgi fragmentation is a common feature in multiple neurodegenerative diseases; however, the precise mechanism that causes remains obscure. A potential link between Cdk5 and Alzheimer's disease (AD) was investigated this study. Because physiologically fragmented during mitosis by Cdc2 kinase current Cdk5-specific chemical inhibitors target as well, development of novel tools to modulate activity essential. These enzyme modulators, created fusing TAT sequence activators an inhibitor peptide,...

Nuclear fragmentation is a common feature in many neurodegenerative diseases, including Alzheimer's disease (AD). In this study, we show that nuclear lamina dispersion an early and irreversible trigger for cell death initiated by deregulated Cdk5, rather than consequence of apoptosis. Cyclin-dependent kinase 5 (Cdk5) activity significantly increased AD contributes to all three hallmarks: neurotoxic amyloid-β (Aβ), neurofibrillary tangles (NFT), extensive death. Using Aβ glutamate as the...

Aurora A kinase is overexpressed in the majority of breast carcinomas. chemical genetic approach was used to identify malignant targets A, which revealed pleckstrin-homology-like domain protein PHLDA1 as an substrate. downregulation a powerful prognostic predictor for carcinoma, confirmed our study. We further show that associated with estrogen receptor (ER) expression carcinoma. directly phosphorylates leading its degradation. also negatively regulates thereby triggering feedback loop....

Cyclin-dependent kinase (Cdk) 5 and p38 activities are significantly increased in Alzheimer's Disease (AD). Both Cdk5 promote neurodegeneration upon deregulation. However, to date the mechanistic link between remains unclear. This study presents first mechanism showing as a major regulator of cascade neurons transgenic mouse model AD. Using beta-amyloid glutamate neurotoxic stimuli, our results show that deregulated induces activation by increasing reactive oxygen species (ROS) neuronal...

Moderate increases of intracellular Ca2+ concentration ([Ca2+]i), induced by either the activation tropomyosin receptor kinase (Trk) receptors for neurotrophins or neuronal activity, regulate different pathways and survival. In present report we demonstrate that glial cell line-derived neurotrophic factor (GDNF) treatment also induces [Ca2+]i elevation mobilizing this cation from internal stores. The effects increase after membrane depolarization are mainly mediated calmodulin (CaM)....

Abstract Heparin‐binding epidermal growth factor‐like factor (HB‐EGF), a vascular‐derived trophic factor, belongs to the (EGF) family of neuroprotective, hypoxia‐inducible proteins released by astrocytes in CNS injuries. It was suggested that HB–EGF can replace fetal calf serum (FCS) astrocyte cultures. We previously demonstrated contrast standard 2D cell culture systems, Bioactive3D system, when used with FCS, minimizes baseline activation and preserves their complex morphology. Here, we...

Restoration of functional connectivity is a major contributor to recovery after stroke. We investigated the role reactive astrocytes in and photothrombotic stroke mice with attenuated gliosis (GFAP–/–Vim–/–). Infarct volume longitudinal changes were determined by vivo T2-weighted magnetic resonance imaging (MRI) resting-state MRI. Sensorimotor function was assessed behavioral tests, glial neural plasticity responses quantified peri-infarct region. Four weeks stroke, GFAP–/–Vim–/– showed...

The type III intermediate filament protein glial fibrillary acidic (GFAP) contributes to the homeostasis of astrocytes, where it co-polymerizes with vimentin. Conversely, alterations in GFAP assembly or degradation cause intracellular aggregates linked astrocyte dysfunction and neurological disease. Moreover, injury inflammation elicit extensive organization expression changes, which underline reactive gliosis. Here we have studied as a target for modification by electrophilic inflammatory...

Microglia and astrocytes have been considered until now as cells with very distinct identities. Here, we assessed the heterogeneity within microglia/monocyte cell population in mouse hippocampus determined their response to injury, by using single-cell gene expression profiling of isolated from uninjured deafferented hippocampus. We found that individual cells, microglial markers Cx3cr1, Aif1, Itgam, Cd68 were co-expressed. Interestingly, injury led co-expression astrocyte marker Gfap a...

The nerve growth factor receptor TrkA (tropomyosin-related kinase receptor) participates in the survival and differentiation of several neuronal populations. C-terminal tail contains a PPXY motif, binding site E3 ubiquitin-ligase Nedd4-2 (neural precursor cell expressed, developmentally down-regulated 4-2). In order to analyze role ubiquitination on function, we generated three mutants, by introducing point mutations conserved hydrophobic amino acids - Leu784 Val790 switched Ala. mutants...

Neuronal signal transduction and communication in vivo is based on highly complex dynamic networks among neurons expanding a three-dimensional (3D) manner. Studies of cell-cell communication, synaptogenesis, neural network plasticity constitute major research areas for understanding the involvement neurodegenerative diseases, such as Huntington's, Alzheimer's, Parkinson's disease, regenerative responses situations, neurotrauma or stroke. Various cell culture systems important experimental...

Vimentin (VIM) is an intermediate filament (nanofilament) protein expressed in multiple cell types, including astrocytes. Mice with VIM mutations of serine sites phosphorylated during mitosis (VIMSA/SA) show cytokinetic failure fibroblasts and lens epithelial cells, chromosomal instability, facilitated senescence, increased neuronal differentiation neural progenitor cells. Here we report that vitro immature VIMSA/SA astrocytes exhibit contain vimentin accumulations co-localize mitochondria....

Astrocytes play a homeostatic role in the central nervous system and influence numerous aspects of neurophysiology via intracellular trafficking vesicles. Intermediate filaments (IFs), also known as nanofilaments, regulate number cellular processes including organelle adult hippocampal neurogenesis. We have recently demonstrated that IF protein nestin, marker neural stem cells immature reactive astrocytes, is expressed some astrocytes unchallenged hippocampus regulates neurogenesis through...

Abstract The tyrosine kinase receptors for the neurotrophins (Trk) are a family of transmembrane that regulate differentiation and survival different neuronal populations. Neurotrophin binding to Trk leads activation several signalling pathways including rapid, but moderate, increase in intracellular calcium levels. We have previously described role its sensor protein, calmodulin, Trk‐activated pathways. Here we demonstrate calmodulin is able precipitate TrkA from PC12 cell lysates. Using...

Abstract Tropomyosin‐related kinase A (TrkA) receptor mediates the effects exerted by nerve growth factor on several subpopulations of neuronal cells. Ligand binding to TrkA induces autophosphorylation tyrosine residues and activation signaling cascades. In this study, we describe a new site relevant for regulation, 701 (Y701), which is important trafficking activation. Y701 replacement aspartate or phenylalanine reduces internalization rate decreases colocalization association with clathrin...

Astrocytes perform a range of homeostatic and regulatory tasks that are critical for normal functioning the central nervous system. In response to an injury or disease, astrocytes undergo pronounced transformation into reactive state involves changes in expression many genes dramatically astrocyte morphology functions. This reactivity is highly dependent on initiating insult pathological context. C3a peptide generated by proteolytic cleavage third complement component. has been shown exert...