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Neurosteroids block the increase in intracellular calcium level induced by Alzheimer’s β-amyloid protein in long-term cultured rat hippocampal neurons
Midori Kato-Negishi,Masahiro Kawahara
Neuropsychiatric Disease and Treatment , 2008,
Abstract: Midori Kato-Negishi1, Masahiro Kawahara21Department of Developmental Morphology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu-shi, Tokyo 183- 8526, Japan; 2Department of Analytical Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino-cho, Nobeoka-shi, Miyazaki 882-8508, JapanAbstract: The neurotoxicity of β-amyloid protein (AβP) is implicated in the etiology of Alzheimer’s disease. We previously have demonstrated that AβP forms Ca2+-permeable pores on neuronal membranes, causes a marked increase in intracellular calcium level, and leads to neuronal death. Here, we investigated in detail the features of AβP-induced changes in intracellular Ca2+ level in primary cultured rat hippocampal neurons using a multisite Ca2+- imaging system with fura-2 as a fluorescent probe. Only a small fraction of short-term cultured hippocampal neurons (ca 1 week in vitro) exhibited changes in intracellular Ca2+ level after AβP exposure. However, AβP caused an acute increase in intracellular Ca2+ level in long-term cultured neurons (ca 1 month in vitro). The responses to AβP were highly heterogeneous, and immunohistochemical analysis using an antibody to AβP revealed that AβP is deposited on some but not all neurons. Considering that the disruption of Ca2+ homeostasis is the primary event in AβP neurotoxicity, substances that protect neurons from an AβP-induced intracellular Ca2+ level increase may be candidates as therapeutic drugs for Alzheimer’s disease. In line with the search for such protective substances, we found that the preadministration of neurosteroids including dehydroepiandrosterone, dehydroepiandrosterone sulfate, and pregnenolone significantly inhibits the increase in intracellular calcium level induced by AβP. Our results suggest the possible significance of neurosteroids, whose levels are reduced in the elderly, in preventing AβP neurotoxicity.Keywords: neurotoxicity, pore, calcium homeostasis, channel, aging
Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid β toxicity
Pedro J Chacon, Rosa Garcia-Mejias, Alfredo Rodriguez-Tebar
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-14
Abstract: We show here that Aβ activates the RhoA GTPase by binding to p75NTR, thereby preventing the NGF-induced activation of protein tyrosine phosphatase 1B (PTP1B) that is required for neuron survival. We also show that the inactivation of RhoA GTPase and the activation of PTP1B protect cultured hippocampal neurons against the noxious effects of Aβ. Indeed, either pharmacological inhibition of RhoA with C3 ADP ribosyl transferase or the transfection of cultured neurons with a dominant negative form of RhoA protects cultured hippocampal neurons from the effects of Aβ. In addition, over-expression of PTP1B also prevents the deleterious effects of Aβ on cultured hippocampal neurons.Our findings indicate that potentiating the activity of NGF at the level of RhoA inactivation and PTP1B activation may represent a new means to combat the noxious effects of Aβ in Alzheimer's disease.According to the amyloid hypothesis, amyloid beta (Aβ) aggregates form deposits in the brain, the process that precipitates the different manifestations of Alzheimer's disease (AD) [1]. Consequently, most therapeutic approaches to treat AD centre on this peptide: on the one hand attempting to limit the production of Aβ or the formation of fibrils and aggregates [2,3], while on the other hand, favouring its clearance. Therapeutic approaches aimed at clearing Aβ plaques have received special attention, and methods for active or passive immunisation have proven effective in reducing Aβ content in the brain. Nevertheless, these strategies have failed to conclusively ameliorate or retard cognitive deterioration in AD patients [4,5].Another approach that could be considered involves blocking the signals induced by Aβ that provoke neuronal death. However, despite extensive studies into the effects of Aβ on neurons, our understanding of Aβ signalling remains fragmented, and a consistent framework for such processes has yet to be defined. Still, recent publications have reinforced the notion that Aβ interferes
Protective effect of spleen-yin-nourishing recipe on amyloid β-peptide-induced damage of primarily cultured rat hippocampal neurons and its mechanism
Li-bin ZHAN
Zhong Xi Yi Jie He Xue Bao , 2009,
Abstract: Objective: To observe the relationship among amyloid β-peptide (Aβ)-induced neurotoxicity, serum-inducible kinase (SNK)-spine-associated Rap guanosine triphosphatase activating protein (SPAR) pathway and N-methyl-D-aspartate receptor (NMDAR), and to explore the mechanism of the protective effect of spleen-yin nourishing recipe (Zibu Piyin Recipe, ZBPYR) in hippocampal neurons against Aβ-induced neurotoxicity.Methods: The Aβ1-40 powder was dissolved in 1×PBS and incubated at 37 ℃, and then aggregated fibrillar Aβ1-40 was obtained 72 h later. We used rat primary hippocampal neurons as cell model. ZBPYR-containing serum was gained by the method of serum pharmacology. ZBPYR-containing serum was added to the culture 1 h before Aβ1-40 (5 μmol/L) exposure. Cells were harvested 2 h after Aβ1-40 exposure for total RNA extracting. Then the mRNA expression levels of SNK, SPAR and NMDAR subunits NR1, NR2A and NR2B were detected by reverse transcription-polymerase chain reaction (RT-PCR).Results: After 2-hour Aβ1-40 exposure, we found that the expression level of SNK mRNA was up-regulated and the expression levels of SPAR, NR1, NR2A and NR2B mRNAs were down-regulated in hippocampal neurons as compared with control group (P<0.01, P<0.05). While with ZBPYR-containing serum pretreatment, the expression level of SNK mRNA was down-regulated and the levels of SPAR, NR1, NR2A and NR2B were up-regulated as compared with Aβ1-40 exposure, and 2% ZBPYR-containing serum showed the best effect (P<0.05). Conclusion: Aβ-induced neurotoxicity was related to SNK-SPAR pathway and NMDAR; ZBPYR-containing serum can protect neurons from Aβ-induced neurotoxicity, and this protective effect may be performed by regulating the expression of NMDAR and blocking of the SNK-SPAR pathway. JCIM Open Access THIS ARTICLE Abstract Full text Download PDF file Send to a friend Related articles in JCIM Cited in JCIM Reader's comments Send a comment
Amyloid-β and Proinflammatory Cytokines Utilize a Prion Protein-Dependent Pathway to Activate NADPH Oxidase and Induce Cofilin-Actin Rods in Hippocampal Neurons  [PDF]
Keifer P. Walsh, Laurie S. Minamide, Sarah J. Kane, Alisa E. Shaw, David R. Brown, Bruce Pulford, Mark D. Zabel, J. David Lambeth, Thomas B. Kuhn, James R. Bamburg
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095995
Abstract: Neurites of neurons under acute or chronic stress form bundles of filaments (rods) containing 1:1 cofilin:actin, which impair transport and synaptic function. Rods contain disulfide cross-linked cofilin and are induced by treatments resulting in oxidative stress. Rods form rapidly (5–30 min) in >80% of cultured hippocampal or cortical neurons treated with excitotoxic levels of glutamate or energy depleted (hypoxia/ischemia or mitochondrial inhibitors). In contrast, slow rod formation (50% of maximum response in ~6 h) occurs in a subpopulation (~20%) of hippocampal neurons upon exposure to soluble human amyloid-β dimer/trimer (Aβd/t) at subnanomolar concentrations. Here we show that proinflammatory cytokines (TNFα, IL-1β, IL-6) also induce rods at the same rate and within the same neuronal population as Aβd/t. Neurons from prion (PrPC)-null mice form rods in response to glutamate or antimycin A, but not in response to proinflammatory cytokines or Aβd/t. Two pathways inducing rod formation were confirmed by demonstrating that NADPH-oxidase (NOX) activity is required for prion-dependent rod formation, but not for rods induced by glutamate or energy depletion. Surprisingly, overexpression of PrPC is by itself sufficient to induce rods in over 40% of hippocampal neurons through the NOX-dependent pathway. Persistence of PrPC-dependent rods requires the continuous activity of NOX. Removing inducers or inhibiting NOX activity in cells containing PrPC-dependent rods causes rod disappearance with a half-life of about 36 min. Cofilin-actin rods provide a mechanism for synapse loss bridging the amyloid and cytokine hypotheses for Alzheimer disease, and may explain how functionally diverse Aβ-binding membrane proteins induce synaptic dysfunction.
Nicotine induces intracellular Ca2+ increases in cultured hippocampal astrocytes by nAChR-dependent and -independent pathways  [PDF]
Miriam Hernández-Morales, Jesús García-Colunga
World Journal of Neuroscience (WJNS) , 2014, DOI: 10.4236/wjns.2014.41005
Abstract:

Nicotine, the major addictive substance in tobacco, interacts with nicotinic acetylcholine receptors (nAChRs) located in neuronal and glial cells, modulating synaptic transmission and memory. Here, we show that nAChRs agonists, including nicotine, acetylcholine, and choline, increase the intracellular Ca2+ concentration ([Ca2+]i) in cultured hippocampal astrocytes, indicating the involvement of nAChRs. Interestingly, inhibition of nAChRs, with a cocktail of antagonists (mecamylamine, methyllycaconitine plus dihydro-β- erythroidine), does not prevent the astrocytic [Ca2+]i increases generated by nicotine. This last effect would be attributable to inhibition of K+ currents by nicotine in these cells, as previously we showed using patch- clamp recordings. Furthermore, the application of tetraethylammonium, an inhibitor of K+ currents, also increases the [Ca2+]i. Together, these results indicate that nicotine increases [Ca2+]i in hippocampal astrocytes through two pathways: by activation of nAChRs, and likely by direct inhibition of K+ currents.

GABA Withdrawal Modifies Network Activity in Cultured Hippocampal Neurons  [PDF]
H. Golan,K. Mikenberg,V. Greenberger,M. Segal
Neural Plasticity , 2000, DOI: 10.1155/np.2000.31
Abstract: Dissociated hippocampal neurons, grown in culture for 2 to 3 weeks, tended to fire bursts of synaptic currents at fairly regular intervals, representing network activity. A brief exposure of cultured neurons to GABA caused a total suppression of the spontaneous network activity. Following a washout of GABA, the activity was no longer clustered in bursts and instead, the cells fired at a high rate tonic manner. The effect of removing GABA could be seen as long as 1 to 2 days after GABA withdrawal and is expressed as an increase in the number of active cells in a network, as well as in their firing rates. Such striking effects of GABA removal may underlie part of the GABA withdrawal syndrome seen elsewhere.
Computational modeling of the effects of amyloid-beta on release probability at hippocampal synapses  [PDF]
Armando Romani,Cristina Marchetti,Daniela Bianchi,Xavier Leinekugel,Panayiota Poirazi,Michele Migliore,Hélène Marie
Frontiers in Computational Neuroscience , 2013, DOI: 10.3389/fncom.2013.00001
Abstract: The role of amyloid beta (Aβ) in brain function and in the pathogenesis of Alzheimer's disease (AD) remains elusive. Recent publications reported that an increase in Aβ concentration perturbs pre-synaptic release in hippocampal neurons. In particular, it was shown in vitro that Aβ is an endogenous regulator of synaptic transmission at the CA3-CA1 synapse, enhancing its release probability. How this synaptic modulator influences neuronal output during physiological stimulation patterns, such as those elicited in vivo, is still unknown. Using a realistic model of hippocampal CA1 pyramidal neurons, we first implemented this Aβ-induced enhancement of release probability and validated the model by reproducing the experimental findings. We then demonstrated that this synaptic modification can significantly alter synaptic integration properties in a wide range of physiologically relevant input frequencies (from 5 to 200 Hz). Finally, we used natural input patterns, obtained from CA3 pyramidal neurons in vivo during free exploration of rats in an open field, to investigate the effects of enhanced Aβ on synaptic release under physiological conditions. The model shows that the CA1 neuronal response to these natural patterns is altered in the increased-Aβ condition, especially for frequencies in the theta and gamma ranges. These results suggest that the perturbation of release probability induced by increased Aβ can significantly alter the spike probability of CA1 pyramidal neurons and thus contribute to abnormal hippocampal function during AD.
EphA4 Activation of c-Abl Mediates Synaptic Loss and LTP Blockade Caused by Amyloid-β Oligomers  [PDF]
Lina M. Vargas, Nancy Leal, Lisbell D. Estrada, Adrian González, Felipe Serrano, Katherine Araya, Katia Gysling, Nibaldo C. Inestrosa, Elena B. Pasquale, Alejandra R. Alvarez
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092309
Abstract: The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-β oligomers (AβOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for AβOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by AβOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to AβOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to AβOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by AβOs. According to this results, the EphA4 antagonistic peptide KYL and c-Abl inhibitor STI prevented i) dendritic spine reduction, ii) the blocking of LTP induction and iii) neuronal apoptosis caused by AβOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by AβOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by AβOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients.
Inhibition of AMPA receptor trafficking at hippocampal synapses by β-amyloid oligomers: the mitochondrial contribution
Yanfang Rui, Jiaping Gu, Kuai Yu, H Criss Hartzell, James Q Zheng
Molecular Brain , 2010, DOI: 10.1186/1756-6606-3-10
Abstract: We found that a brief exposure of hippocampal neurons to Aβ oligomers not only led to marked removal of AMPARs from postsynaptic surface but also impaired rapid AMPAR insertion during chemically-induced synaptic potentiation. We also found that Aβ oligomers exerted acute impairment of fast mitochondrial transport, as well as mitochondrial translocation into dendritic spines in response to repetitive membrane depolarization. Quantitative analyses at the single spine level showed a positive correlation between spine-mitochondria association and the surface accumulation of AMPARs. In particular, we found that spines associated with mitochondria tended to be more resistant to Aβ inhibition on AMPAR trafficking. Finally, we showed that inhibition of GSK3β alleviated Aβ impairment of mitochondrial transport, and effectively abolished Aβ-induced AMPAR loss and inhibition of AMPAR insertion at spines during cLTP.Our findings indicate that mitochondrial association with dendritic spines may play an important role in supporting AMPAR presence on or trafficking to the postsynaptic membrane. Aβ disruption of mitochondrial trafficking could contribute to AMPAR removal and trafficking defects leading to synaptic inhibition.Alzheimer's disease (AD) often attacks aged populations and is highlighted by progressive loss of memory and cognitive abilities [4]. AD brains exhibit two major pathological hallmarks: extracellular senile plaques containing β-amyloid aggregates and intracellular neurofibrillary tangles consisting of hyperphosphorylated microtubule-associated tau proteins [5,6]. β-amyloid (Aβ) molecules are generated by proteolytic cleavage of the transmembrane β-amyloid precursor protein (APP) [7,8]. Aggregated Aβ fibrils constitute the core of neuritic plaques and are believed to be a major culprit for neurodegeneration and subsequent cognitive abnormalities in AD patients [9-11]. Recent studies, however, indicate that Aβ molecules exert adverse effects on neuronal functions
Concentration-dependent effects of fullerenol on cultured hippocampal neuron viability
Zha YY, Yang B, Tang ML, Guo QC, Chen JT, Wen LP, Wang M
International Journal of Nanomedicine , 2012, DOI: http://dx.doi.org/10.2147/IJN.S30934
Abstract: ncentration-dependent effects of fullerenol on cultured hippocampal neuron viability Original Research (2460) Total Article Views Authors: Zha YY, Yang B, Tang ML, Guo QC, Chen JT, Wen LP, Wang M Published Date June 2012 Volume 2012:7 Pages 3099 - 3109 DOI: http://dx.doi.org/10.2147/IJN.S30934 Received: 16 February 2012 Accepted: 17 April 2012 Published: 29 June 2012 Ying-ying Zha,1 Bo Yang,1 Ming-liang Tang,2 Qiu-chen Guo,1 Ju-tao Chen,1 Long-ping Wen,3 Ming Wang1 1CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 2Suzhou Institute of NanoTech and NanoBionics, Chinese Academy of Sciences, Suzhou, 3Laboratory of Nano-biology, School of Life Sciences, University of Science and Technology of China, Hefei, People's Republic of China Background: Recent studies have shown that the biological actions and toxicity of the water-soluble compound, polyhydroxyfullerene (fullerenol), are related to the concentrations present at a particular site of action. This study investigated the effects of different concentrations of fullerenol on cultured rat hippocampal neurons. Methods and results: Fullerenol at low concentrations significantly enhanced hippocampal neuron viability as tested by MTT assay and Hoechst 33342/propidium iodide double stain detection. At high concentrations, fullerenol induced apoptosis confirmed by Comet assay and assessment of caspase proteins. Conclusion: These findings suggest that fullerenol promotes cell death and protects against cell damage, depending on the concentration present. The concentration-dependent effects of fullerenol were mainly due to its influence on the reduction-oxidation pathway.
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