scholarly journals Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Bianca Seifert ◽  
Robert Eckenstaler ◽  
Raik Rönicke ◽  
Julia Leschik ◽  
Beat Lutz ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Hippocampal Neurons ◽  
Early Time ◽  
Retrograde Transport ◽  
Secretory Protein ◽  
Adult Brain ◽  
Model Systems ◽  
Extracellular Medium ◽  
Transgenic Expression ◽  
Brain Functions

The neurotrophin brain derived neurotrophic factor (BDNF) is an important growth factor in the CNS. Deficits in transport of this secretory protein could underlie neurodegenerative diseases. Investigation of disease-related changes in BDNF transport might provide insights into the cellular mechanism underlying, for example, Alzheimer’s disease (AD). To analyze the role of BDNF transport in AD, live cell imaging of fluorescently labeled BDNF was performed in hippocampal neurons of different AD model systems. BDNF and APP colocalized with low incidence in vesicular structures. Anterograde as well as retrograde transport of BDNF vesicles was reduced and these effects were mediated by factors released from hippocampal neurons into the extracellular medium. Transport of BDNF was altered at a very early time point after onset of human APP expression or after acute amyloid-beta(1-42) treatment, while the activity-dependent release of BDNF remained unaffected. Taken together, extracellular cleavage products of APP induced rapid changes in anterograde and retrograde transport of BDNF-containing vesicles while release of BDNF was unaffected by transgenic expression of mutated APP. These early transport deficits might lead to permanently impaired brain functions in the adult brain.

scholarly journals Telomerase increasing compound protects hippocampal neurons from amyloid beta toxicity by enhancing the expression of neurotrophins and plasticity related genes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Natalie Baruch-Eliyahu ◽  
Vladislav Rud ◽  
Alex Braiman ◽  
Esther Priel
Keyword(s):  
Oxidative Stress ◽  
Amyloid Beta ◽  
Neurotrophic Factors ◽  
Hippocampal Neurons ◽  
Neuroprotective Effect ◽  
Adult Brain ◽  
Beta Catenin ◽  
Adult Mice ◽  
Hippocampal Cell Culture ◽  
Neuronal Degradation

AbstractThe telomerase reverse transcriptase protein, TERT, is expressed in the adult brain and its exogenic expression protects neurons from oxidative stress and from the cytotoxicity of amyloid beta (Aβ). We previously showed that telomerase increasing compounds (AGS) protected neurons from oxidative stress. Therefore, we suggest that increasing TERT by AGS may protect neurons from the Aβ-induced neurotoxicity by influencing genes and factors that participate in neuronal survival and plasticity. Here we used a primary hippocampal cell culture exposed to aggregated Aβ and hippocampi from adult mice. AGS treatment transiently increased TERT gene expression in hippocampal primary cell cultures in the presence or absence of Aβ and protected neurons from Aβ induced neuronal degradation. An increase in the expression of Growth associated protein 43 (GAP43), and Feminizing locus on X-3 genes (NeuN), in the presence or absence of Aβ, and Synaptophysin (SYP) in the presence of Aβ was observed. GAP43, NeuN, SYP, Neurotrophic factors (NGF, BDNF), beta-catenin and cyclin-D1 expression were increased in the hippocampus of AGS treated mice. This data suggests that increasing TERT by pharmaceutical compounds partially exerts its neuroprotective effect by enhancing the expression of neurotrophic factors and neuronal plasticity genes in a mechanism that involved Wnt/beta-catenin pathway.

scholarly journals Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice

2017 ◽  
Vol 114 (4) ◽  
pp. E619-E628 ◽  
Author(s):  
Chih-Ming Chen ◽  
Lauren L. Orefice ◽  
Shu-Ling Chiu ◽  
Tara A. LeGates ◽  
Samer Hattar ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Spatial Learning ◽  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Neuronal Morphology ◽  
Adult Brain ◽  
Receptor Expression ◽  
Spatial Learning And Memory ◽  
Brain Functions ◽  
Wnt5a Expression

Stability of neuronal connectivity is critical for brain functions, and morphological perturbations are associated with neurodegenerative disorders. However, how neuronal morphology is maintained in the adult brain remains poorly understood. Here, we identify Wnt5a, a member of the Wnt family of secreted morphogens, as an essential factor in maintaining dendritic architecture in the adult hippocampus and for related cognitive functions in mice. Wnt5a expression in hippocampal neurons begins postnatally, and its deletion attenuated CaMKII and Rac1 activity, reduced GluN1 glutamate receptor expression, and impaired synaptic plasticity and spatial learning and memory in 3-mo-old mice. With increased age, Wnt5a loss caused progressive attrition of dendrite arbors and spines in Cornu Ammonis (CA)1 pyramidal neurons and exacerbated behavioral defects. Wnt5a functions cell-autonomously to maintain CA1 dendrites, and exogenous Wnt5a expression corrected structural anomalies even at late-adult stages. These findings reveal a maintenance factor in the adult brain, and highlight a trophic pathway that can be targeted to ameliorate dendrite loss in pathological conditions.

Two Mechanisms That Raise Free Intracellular Calcium in Rat Hippocampal Neurons During Hypoosmotic and Low NaCl Treatment

2000 ◽  
Vol 83 (1) ◽  
pp. 81-89 ◽  
Author(s):  
Aren J. Borgdorff ◽  
George G. Somjen ◽  
Wytse J. Wadman
Keyword(s):  
Synaptic Transmission ◽  
Intracellular Calcium ◽  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Cell Swelling ◽  
Tissue Slices ◽  
Extracellular Medium ◽  
Calcium Activity ◽  
Hippocampal Pyramidal Neurons

Previous studies have shown that exposing hippocampal slices to low osmolarity (πo) or to low extracellular NaCl concentration ([NaCl]o) enhances synaptic transmission and also causes interstitial calcium ([Ca2+]o) to decrease. Reduction of [Ca2+]o suggests cellular uptake and could explain the potentiation of synaptic transmission. We measured intracellular calcium activity ([Ca2+]i) using fluorescent indicator dyes. In CA1 hippocampal pyramidal neurons in tissue slices, lowering πo by ∼70 mOsm caused “resting” [Ca2+]i as well as synaptically or directly stimulated transient increases of calcium activity (Δ[Ca2+]i) to transiently decrease and then to increase. In dissociated cells, lowering πo by ∼70 mOsm caused [Ca2+]i to almost double on average from 83 to 155 nM. The increase of [Ca2+]i was not significantly correlated with hypotonic cell swelling. Isoosmotic (mannitol- or sucrose-substituted) lowering of [NaCl]o, which did not cause cell swelling, also raised [Ca2+]i. Substituting NaCl with choline-Cl or Na-methyl-sulfate did not affect [Ca2+]i. In neurons bathed in calcium-free medium, lowering πo caused a milder increase of [Ca2+]i, which was correlated with cell swelling, but in the absence of external Ca2+, isotonic lowering of [NaCl]o triggered only a brief, transient response. We conclude that decrease of extracellular ionic strength (i.e., in both low πo and low [NaCl]o) causes a net influx of Ca2+ from the extracellular medium whereas cell swelling, or the increase in membrane tension, is a signal for the release of Ca2+ from intracellular stores.

scholarly journals Lack of Fusion of Azurophil Granules with Phagosomes during Phagocytosis of Mycobacterium smegmatis by Human Neutrophils Is Not Actively Controlled by the Bacterium

2002 ◽  
Vol 70 (3) ◽  
pp. 1591-1598 ◽  
Author(s):  
Céline Cougoule ◽  
Patricia Constant ◽  
Gilles Etienne ◽  
Mamadou Daffé ◽  
Isabelle Maridonneau-Parini
Keyword(s):  
Mycobacterium Smegmatis ◽  
Early Time ◽  
Immune Serum ◽  
Human Neutrophils ◽  
Dependent Manner ◽  
Extracellular Medium ◽  
Lack Of Fusion ◽  
Large Clusters ◽  
Secretory Lysosomes ◽  
Neutrophil Surface

ABSTRACT Biogenesis of phagolysosomes is a very rapid event in neutrophils which takes place with nascent unclosed phagosomes, leading to the release of lysosomal enzymes such as β-glucuronidase in the extracellular medium. We have previously shown that, under nonopsonic conditions, both pathogenic and nonpathogenic mycobacteria uncouple phagocytosis from fusion of azurophil granules (specialized secretory lysosomes) with phagosomes. In the present study we questioned whether they actively act on neutrophils to block this process or use phagocytic receptors that negatively control the biogenesis of phagolysosomes. As for live unicellular Mycobacterium smegmatis, we observed that nonopsonic phagocytosis of heat-killed mycobacteria did not induce the release of β-glucuronidase, indicating that M. smegmatis does not actively act on the fusion process in neutrophils. In contrast, phagocytosis of unicellular M. smegmatis opsonized in immune serum or that of small nonopsonized mycobacterial aggregates restored the biogenesis of phagolysosomes. Aggregates were internalized in a CR3- and cholesterol-dependent manner as unicellular mycobacteria. However, aggregates but not unicellular bacteria triggered F-actin and Hck recruitment at the phagosomes, events that have been associated with lysosome fusion. Thus, we propose that M. smegmatis does not actively control the fusion of azurophil granules at early time points postinfection and that mycobacterial aggregates recruit large clusters of receptors at the neutrophil surface which could trap proteins implicated in the biogenesis of phagolysosomes.

Stimulus-Secretion Coupling: A Perspective Highlighting the Contributions of Peter Baker

1988 ◽  
Vol 139 (1) ◽  
pp. 1-30
Author(s):  
T. J. RINK ◽  
D. E. KNIGHT
Keyword(s):  
Fluorescent Dyes ◽  
Motor Nerve ◽  
Giant Axon ◽  
Model Systems ◽  
Motor Nerve Terminal ◽  
Coupling Mechanism ◽  
Extracellular Medium ◽  
Adrenal Chromaffin Cell ◽  
Intact Cells ◽  
Stimulus Secretion Coupling

Many investigators are using numerous preparations for contributing to our present understanding of stimulus-secretion coupling, by which we mean stimulus-dependent exocytosis, sometimes known as the regulated pathway. However, a few model systems have been particularly illuminating and several of these were exploited by Peter Baker and his close associates: namely, the motor nerve terminal, the adrenal chromaffin cell, the sea urchin egg and the blood platelet. In fact, Peter's first real contribution in this area came from his seminal studies on calcium transport in his favourite preparation, the squid giant axon, where he investigated Ca2+/Na+ exchange, Ca2+ distribution and voltage-gated Ca2+ entry. More direct investigations into stimulus-secretion coupling came from work on neurone transmitter release in collaboration with Andrew Crawford, and on catecholamine secretion from the adrenal medulla in collaboration (with TJR). His most important generic contribution to this field was in the development (with DEK), of the electropermeabilized cell, which allows control of the low molecular weight components of the cytosol while leaving the exocytotic apparatus and process intact. In the initial experiments on the cells it was finally proved that Ca2+-dependent secretion of catecholamines is indeed from the granules and not from the cytosol. The quantification of the Ca2+ requirement of secretory exocytosis was an important step, as was the investigation of many factors purported to be important in the coupling mechanism or in the exocytotic process itself. Work with the human platelet, using this technique, has proved to be especially valuable in unravelling the complex interactions between different second messengers and has been neatly complemented by work in intact cells containing Ca2+-indicator fluorescent dyes. Peter was also intrigued by postsecretory events both in the early seventies, and at the end of his career when he embarked on analysis of the membrane retrieval process and the associated uptake of extracellular medium.

Organelle motility and metabolism in axons vs dendrites of cultured hippocampal neurons

1996 ◽  
Vol 109 (5) ◽  
pp. 971-980 ◽  
Author(s):  
C.C. Overly ◽  
H.I. Rieff ◽  
P.J. Hollenbeck
Keyword(s):  
Regional Variation ◽  
Hippocampal Neurons ◽  
Retrograde Transport ◽  
Organelle Transport ◽  
Microtubule Polarity ◽  
Large Phase ◽  
Organelle Motility ◽  
The Difference ◽  
Metabolic Properties ◽  
Cultured Hippocampal Neurons

Regional regulation of organelle transport seems likely to play an important role in establishing and maintaining distinct axonal and dendritic domains in neurons, and in managing differences in local metabolic demands. In addition, known differences in microtubule polarity and organization between axons and dendrites along with the directional selectivity of microtubule-based motor proteins suggest that patterns of organelle transport may differ in these two process types. To test this hypothesis, we compared the patterns of movement of different organelle classes in axons and different dendritic regions of cultured embryonic rat hippocampal neurons. We first examined the net direction of organelle transport in axons, proximal dendrites and distal dendrites by video-enhanced phase-contrast microscopy. We found significant regional variation in the net transport of large phase-dense vesicular organelles: they exhibited net retrograde transport in axons and distal dendrites, whereas they moved equally in both directions in proximal dendrites. No significant regional variation was found in the net transport of mitochondria or macropinosomes. Analysis of individual organelle motility revealed three additional differences in organelle transport between the two process types. First, in addition to the difference in net transport direction, the large phase-dense organelles exhibited more persistent changes in direction in proximal dendrites where microtubule polarity is mixed than in axons where microtubule polarity is uniform. Second, while the net direction of mitochondrial transport was similar in both processes, twice as many mitochondria were motile in axons than in dendrites. Third, the mean excursion length of moving mitochondria was significantly longer in axons than in dendrites. To determine whether there were regional differences in metabolic activity that might account for these motility differences, we labeled mitochondria with the vital dye, JC-1, which reveals differences in mitochondrial transmembrane potential. Staining of neurons with this dye revealed a greater proportion of highly charged, more metabolically active, mitochondria in dendrites than in axons. Together, our data reveal differences in organelle motility and metabolic properties in axons and dendrites of cultured hippocampal neurons.

scholarly journals Circuit Integration Initiation of New Hippocampal Neurons in the Adult Brain

Cell Reports ◽  
2020 ◽  
Vol 30 (4) ◽  
pp. 959-968.e3 ◽  
Author(s):  
Chih-Hao Yang ◽  
Adrian Di Antonio ◽  
Gregory W. Kirschen ◽  
Parul Varma ◽  
Jenny Hsieh ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Adult Brain ◽  
Circuit Integration

scholarly journals Chemical LTD, but not LTP, induces transient accumulation of gelsolin in dendritic spines

2019 ◽  
Vol 400 (9) ◽  
pp. 1129-1139 ◽  
Author(s):  
Iryna Hlushchenko ◽  
Pirta Hotulainen
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Long Term Potentiation ◽  
Excitatory Synapses ◽  
Signal Molecule ◽  
Brain Functions ◽  
Dendritic Shaft ◽  
Term Potentiation

Abstract Synaptic plasticity underlies central brain functions, such as learning. Ca2+ signaling is involved in both strengthening and weakening of synapses, but it is still unclear how one signal molecule can induce two opposite outcomes. By identifying molecules, which can distinguish between signaling leading to weakening or strengthening, we can improve our understanding of how synaptic plasticity is regulated. Here, we tested gelsolin’s response to the induction of chemical long-term potentiation (cLTP) or long-term depression (cLTD) in cultured rat hippocampal neurons. We show that gelsolin relocates from the dendritic shaft to dendritic spines upon cLTD induction while it did not show any relocalization upon cLTP induction. Dendritic spines are small actin-rich protrusions on dendrites, where LTD/LTP-responsive excitatory synapses are located. We propose that the LTD-induced modest – but relatively long-lasting – elevation of Ca2+ concentration increases the affinity of gelsolin to F-actin. As F-actin is enriched in dendritic spines, it is probable that increased affinity to F-actin induces the relocalization of gelsolin.

Rescue of Prothrombin-deficiency by Transgene Expression in Mice

2002 ◽  
Vol 88 (12) ◽  
pp. 984-991 ◽  
Author(s):  
William Sun ◽  
Mallory Coleman ◽  
David Witte ◽  
Sandra Degen
Keyword(s):  
Transgenic Mice ◽  
Transgene Expression ◽  
Embryonic Lethality ◽  
The Other ◽  
Model Systems ◽  
Bleeding Events ◽  
Specific Expression ◽  
Spontaneous Bleeding ◽  
Knock Out ◽  
Transgenic Expression

SummaryProthrombin has diverse biological functions in addition to its well established role in blood coagulation. In order to study these functions in more detail mouse model systems are needed. Since deficiency of prothrombin in mice results in partial embryonic lethality and neonatal death, alternative approaches are required to study the biology of prothrombin in the adult mouse. The liver is the major site of synthesis of prothrombin and therefore liver-specific promoters were used to express prothrombin in transgenic mice. Mice generated from crosses with these transgenic mice and mice hemizygous for the knock-out allele were used to test whether liver-specific expression is sufficient to correct the phenotype of null mice and whether liver-specific expression is sufficient for the development and survival of mice to adulthood. The mouse albumin promoter/enhancer was used initially for transgene expression without success in obtaining transgene positive, endogenous prothrombin null mice. Two lines of transgene positive, endogenous prothrombin deficient mice were obtained using the mouse transthyretin (TTR) promoter/enhancer driving expression of a human prothrombin cDNA. One line was able to rescue both the embryonic and the neonatal lethality while the other line was only able to correct the embryonic lethality. Expression of prothrombin was restricted to the liver and stomach in one line and to the liver, pancreas, stomach and kidney in the other line of mice. Thrombin activity for one line was determined to be at 5-10% of wildtype levels. These mice developed normally and did not have spontaneous bleeding events unless traumatized. Therefore, transgenic expression of human prothrombin is sufficient for the rescue of the lethality found for prothrombin deficiency in mice.

NFIX-Mediated Inhibition of Neuroblast Branching Regulates Migration Within the Adult Mouse Ventricular–Subventricular Zone

2018 ◽  
Vol 29 (8) ◽  
pp. 3590-3604 ◽  
Author(s):  
Oressia Zalucki ◽  
Lachlan Harris ◽  
Tracey J Harvey ◽  
Danyon Harkins ◽  
Jocelyn Widagdo ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Subventricular Zone ◽  
Adult Mouse ◽  
Adult Brain ◽  
Granule Cell Layer ◽  
Transcriptional Level ◽  
Olfactory Responses ◽  
Brain Functions ◽  
Neuroblast Migration ◽  
Adult Mice

Abstract Understanding the migration of newborn neurons within the brain presents a major challenge in contemporary biology. Neuronal migration is widespread within the developing brain but is also important within the adult brain. For instance, stem cells within the ventricular–subventricular zone (V-SVZ) and the subgranular zone of dentate gyrus of the adult rodent brain produce neuroblasts that migrate to the olfactory bulb and granule cell layer of the dentate gyrus, respectively, where they regulate key brain functions including innate olfactory responses, learning, and memory. Critically, our understanding of the factors mediating neuroblast migration remains limited. The transcription factor nuclear factor I X (NFIX) has previously been implicated in embryonic cortical development. Here, we employed conditional ablation of Nfix from the adult mouse brain and demonstrated that the removal of this gene from either neural stem and progenitor cells, or neuroblasts, within the V-SVZ culminated in neuroblast migration defects. Mechanistically, we identified aberrant neuroblast branching, due in part to increased expression of the guanylyl cyclase natriuretic peptide receptor 2 (Npr2), as a factor contributing to abnormal migration in Nfix-deficient adult mice. Collectively, these data provide new insights into how neuroblast migration is regulated at a transcriptional level within the adult brain.

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