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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of nerve growth factor (NGF) using adenoviruses (Adts) after spinal cord injury induces extensive regeneration and sprouting of calcitonin-gene-related peptide immunoreactive (CGRP-IR) fibers, whereas overexpression of cell adhesion molecules (CAMs) has no effect on the normal distribution of these fibers. Interestingly, co-expression of cell adhesion molecule L1 and NGF significantly decreases (p<0.0001) CGRP-IR fiber sprouting within the spinal cord, when compared to NGF alone. Co-expression of cell adhesion molecules NCAM or N-cadherin had no effect on NGF-induced CGRP-IR fiber sprouting. These data demonstrate that reduced sprouting is specific to L1 co-expression and not other cell adhesion molecules. In vitro studies carried out to address potential mechanisms show that neurite outgrowth over astrocytes overexpressing L1 in the presence of NGF is comparable to controls, indicating that other factors present in vivo might be involved in the L1-mediated reduction in sprouting. One potential factor is semaphorin 3A (sema3A), which mediates growth cone collapse of CGRP-positive axons. Recent studies have shown that L1 is important in sema3A receptor signaling for cortical neurons. In our study, co-expression of sema3A indeed reduces neurite outgrowth from DRG neurons by about 40% on L1-expressing astrocytes. Based on these results, we hypothesize that overexpression of L1 potentiates sema3A signaling resulting in reduced sprouting.
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PMID:Cell adhesion molecule L1 modulates nerve-growth-factor-induced CGRP-IR fiber sprouting. 1686 Mar 20

Hair follicles (HFs) enjoy a relative immune privilege (IP) that is characterized by downregulation of major histocompatibility complex (MHC) class I and local expression of potent immunosuppressants. Normally, natural killer (NK) cells attack cells with absent/low MHC class I expression. However, because few perifollicular NK cells are found around healthy human anagen HFs, we asked how HFs escape from NK cell attack. This study suggests that this happens via an active NK cell suppression. Alopecia areata (AA), an organ-specific autoimmune disease thought to result from a collapse of HF-IP, in contrast, shows striking defects in NK cell inhibition/containment. We show that the NK cell inhibitor macrophage migration inhibitory factor is strongly expressed by the HF epithelium, and very few CD56(+)/NKG2D(+) NK cells are observed in and around normal anagen HFs compared to AA with prominent aggregations of CD56(+)/NKG2D(+) NK around AA-HFs. By flow cytometry, many fewer NK function-activating receptors (NKG2D, NKG2C) and significantly more killer cell Ig-like receptors-2D2/2D3 were found to be expressed on peripheral blood CD56(+) NK cells of healthy controls than on those of AA patients. In addition, only weak immunoreactivity for MHC class I chain-related A gene was observed in normal anagen HFs compared to AA. To our knowledge, this defect is previously unreported and must be taken into account in AA pathogenesis and its management.
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PMID:Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack. 1816 Sep 67

Granzyme K (Gzm K) and granzyme A (GzmA) are the only two tryptases among all the granzymes. Tryptase activity is necessary for cytotoxic T lymphocyte (CTL)/nature killer (NK) cells-mediated cytolysis. Granzyme K might be a potent granzyme to rescue the activity of granzyme A. Granzyme K expresses at high levels in CD56(high) NK cells, memory CD8+ T cells and CD56+ T cells. We recently demonstrated human granzyme K induces rapid cell death with rapid externalization of phosphatidylserine, nuclear morphological changes and single-stranded DNA nicks. Moreover, Granzyme K can induce rapid reactive oxygen species (ROS) generation and collapse of mitochondrial inner membrane potential. Blockade of reactive oxygen species accumulation suppresses granzyme K-induced cell death. However, it is unknown about how reactive oxygen species generate in Granzyme K-mediated apoptosis. Here we found the redox factor-1/apurinic apyrimidinic endonuclease Ape1 can antagonize reactive oxygen species generation. Overexpression of Ape1 inhibits, whereas silencing Ape1 expression potentiates reactive oxygen species accumulation under treatment with oxidative reagents or loading with granzyme K. Ape1 is a physiological substrate of granzyme K. Ape1 cleavage by granzyme K facilitates intracellular reactive oxygen species accumulation and enhances granzyme K-induced cell death.
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PMID:Granzyme K degrades the redox/DNA repair enzyme Ape1 to trigger oxidative stress of target cells leading to cytotoxicity. 1817 23

GAP-43 is the major neuronal substrate of protein kinase C (PKC). Its phosphorylation status dictates the severity of pathfinding errors by GAP-43 (+/-) growth cones in vivo, as well as its modulation of actin dynamics in vitro. These experiments show that stably overexpressing cDNAs mutant at its single PKC phosphorylation site at serine41 in retinoic acid treated SH-Sy5Y neuroblastoma cells regulates intrinsic and extrinsic behaviors of growing neurons. Intrinsically, only Wt and pseudophosphorylated GAP-43Ser41Asp precipitated with F-actin and potentiated F-actin - regulated filopodia formation. GAP-43Ser41Asp inhibited neurite outgrowth whereas only unphosphorylatable GAP-43Ser41Ala precipitated neurotubulin, potentiated neurotubulin accumulation in neurites and increased outgrowth. When PI3-kinase was inhibited GAP-43Ser41Asp-mediated filopodia formation was inhibited whereas GAP-43Ser41Ala-mediated neurite extension was potentiated. Extrinsically, only Wt and GAP-43Ser41Asp potentiated both homotypic adhesion and neurite outgrowth on NCAM-expressing monolayers and promoted NCAM stability. With respect to the underlying mechanism, more F-actin and NCAM colocalized with Wt and GAP-43Ser41Asp in detergent resistant membranes (DRMs) isolated from live cells and GAP-43Ser41Asp-mediated functions were insensitive to cholesterol depletion. In contrast, GAP-43Ser41Ala-mediated functions were sensitive to cholesterol depletion. Neither GAP-43Ser41Asp nor GAP-43Ser41Ala was able to protect against growth cone collapse mediated by PIP2 inhibitors. The results show that modification of GAP-43 at its PKC phosphorylation site directs its distribution to different membrane microdomains that have distinct roles in the regulation of intrinsic and extrinsic behaviors in growing neurons.
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PMID:Regulation of GAP-43 at serine 41 acts as a switch to modulate both intrinsic and extrinsic behaviors of growing neurons, via altered membrane distribution. 1924 69

Visual activity acts via NMDA Receptors to refine developing retinotectal maps by shaping retinal arbors. Retinal axons add and delete transient branches, and the dynamic rates increase when MK801 blocks NMDARs, as if this prevents release of a stabilizing signal. Ca(++) entry through NMDARs activates phospholipase A2 (cPLA2) to release arachidonic acid (AA), which taps into a presynaptic growth control mechanism. NCAM, L1, N-cadherin, and FGF all stimulate axon growth via AA activation of protein kinase C to phosphorylate GAP43 and polymerize/stabilize F-actin. Our previous results show that blocking cPLA2 mimics NMDAR blockers, whereas exogenous AA reverses the increased dynamics, and PKC inhibitors also arrest growth. To test whether this activity-driven F-actin control mechanism shapes retinotectal arbors in zebrafish, we used the alpha-1-tubulin promoter to express GAP43-GFP fusion proteins in retinal ganglion cells, and imaged arbors in time-lapse to test for effects of GAP43 levels and its phosphorylation. Overexpressing wildtype GAP43 gave faster growth and larger arbors (#branches, spatial extent, total length of branches) at three days and especially four days. Surprisingly, the N-terminal 20 amino acid segment alone caused the same increase in branching, but no increase in growth. Earlier studies implicate this region in activating G(o) resulting in collapse of growth cones, which is now known to precede branch initiation. In contrast, GAP43 with ser41 mutated to ala (S41A) to prevent phosphorylation did not increase either branching or growth but resulted in immature, elongated arbors even at four to five days. In support of this atrophic effect, only half of brain/spinal neurons expressing S41A successfully initiated axonal outgrowth (vs. nearly 100% for wtGAP43). These results suggest that the region around the ser41 phosphorylation site, which binds CaM and PIP2, promotes growth only when phosphorylated, and also activates the branching control region in the first 10-20 amino acids. Whereas phosphorylation introduces a bulky negative charge group, mutation of serine to arginine introduces a bulky positive charge. But this also produced the same growth and branching as phosphorylation, suggesting that the effect of phosphorylation is through hydrophilic bulk rather than negative charge, in agreement with other IQ motifs. The results implicate the cPLA2-AA-PKC-GAP43 pathway as part of an F-actin based mechanism that both stabilizes new synapses and initiates new branches near effective synapses.
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PMID:GAP43 phosphorylation is critical for growth and branching of retinotectal arbors in zebrafish. 2066 23

Alzheimer's disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD.
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PMID:Increased Levels of Brain Adrenomedullin in the Neuropathology of Alzheimer's Disease. 2886 32

Perineuronal nets (PNNs) are implicated in closure of critical periods of synaptic plasticity in the brain, but the molecular mechanisms by which PNNs regulate synapse development are obscure. A receptor complex of NCAM and EphA3 mediates postnatal remodeling of inhibitory perisomatic synapses of GABAergic interneurons onto pyramidal cells in the mouse frontal cortex necessary for excitatory/inhibitory balance. Here it is shown that enzymatic removal of PNN glycosaminoglycan chains decreased the density of GABAergic perisomatic synapses in mouse organotypic cortical slice cultures. Neurocan, a key component of PNNs, was expressed in postnatal frontal cortex in apposition to perisomatic synapses of parvalbumin-positive interneurons. Polysialylated NCAM (PSA-NCAM), which is required for ephrin-dependent synapse remodeling, bound less efficiently to neurocan than mature, non-PSA-NCAM. Neurocan bound the non-polysialylated form of NCAM at the EphA3 binding site within the immunoglobulin-2 domain. Neurocan inhibited NCAM/EphA3 association, membrane clustering of NCAM/EphA3 in cortical interneuron axons, EphA3 kinase activation, and ephrin-A5-induced growth cone collapse. These studies delineate a novel mechanism wherein neurocan inhibits NCAM/EphA3 signaling and axonal repulsion, which may terminate postnatal remodeling of interneuron axons to stabilize perisomatic synapses in vivo.
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PMID:Perineuronal Net Protein Neurocan Inhibits NCAM/EphA3 Repellent Signaling in GABAergic Interneurons. 2967 Jan 69

Parvalbumin (PV)-expressing basket interneurons in the prefrontal cortex (PFC) regulate pyramidal cell firing, synchrony, and network oscillations. Yet, it is unclear how their perisomatic inputs to pyramidal neurons are integrated into neural circuitry and adjusted postnatally. Neural cell adhesion molecule NCAM is expressed in a variety of cells in the PFC and cooperates with EphrinA/EphAs to regulate inhibitory synapse density. Here, analysis of a novel parvalbumin (PV)-Cre: NCAM F/F mouse mutant revealed that NCAM functions presynaptically in PV+ basket interneurons to regulate postnatal elimination of perisomatic synapses. Mutant mice exhibited an increased density of PV+ perisomatic puncta in PFC layer 2/3, while live imaging in mutant brain slices revealed fewer puncta that were dynamically eliminated. Furthermore, EphrinA5-induced growth cone collapse in PV+ interneurons in culture depended on NCAM expression. Electrophysiological recording from layer 2/3 pyramidal cells in mutant PFC slices showed a slower rise time of inhibitory synaptic currents. PV-Cre: NCAM F/F mice exhibited impairments in working memory and social behavior that may be impacted by altered PFC circuitry. These findings suggest that the density of perisomatic synapses of PV+ basket interneurons is regulated postnatally by NCAM, likely through EphrinA-dependent elimination, which is important for appropriate PFC network function and behavior.
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PMID:Developmental Regulation of Basket Interneuron Synapses and Behavior through NCAM in Mouse Prefrontal Cortex. 3224 96