Sanders-Brown Research Center on Aging and Department of Anatomy & Neurobiology, University of Kentucky, Lexington, KY 40536, USA
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Abstract |
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Introduction |
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The production of several different neurotrophic factors is induced by neuronal activity (Thoenen, 1995), and these neurotrophic factors can, in turn, modulate neuronal survival and plasticity (Mattson and Lindvall, 1997
). A remarkable number of neurotrophic factors have been found to protect neurons in cell culture and in vivo against various excitotoxic, metabolic and oxidative insults (Mattson and Scheff, 1994
). For example, basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor, nerve growth factor (NGF) and activity-dependent neurotrophic factor (ADNF) can protect neurons against excitotoxic and metabolic insults in cell culture (Mattson et al., 1989
; Cheng and Mattson, 1991
; Brenneman and Gozes, 1996
; Brenneman et al., 1998a
), and against ischemic brain injury in vivo (Shigeno et al., 1991
; Nozaki et al., 1993
; Guegan et al., 1998
). The mechanisms whereby neurotrophic factors protect neurons are thought to involve modulation of expression (at the transcriptional level) of genes encoding antioxidant enzymes (Mattson et al., 1995
), calcium-regulating proteins (Cheng et al., 1994
) and anti-apoptotic factors such as Bcl-2 (Allsopp et al., 1995
). While it is well-established that neurotrophic factors can engage signaling pathways linked to transcription factor activation (Segal and Greenberg, 1996
), it is not known whether neurotrophic factors can exert local (transcription-independent) actions in synaptic compartments. Although synapses are sites at which the neuroprotective actions of activity-dependent neurotrophic factors would seem most likely to be exerted, it is not known whether such factors can act at the level of the synapse, independently of the cell body. However, it was recently reported that the secreted form of amyloid precursor protein can exert direct neuroprotective actions in synaptic terminals (Mattson et al., 1999
), suggesting the possibility that other neurotrophic factors may have similar actions. In the present study we show that nine amino acid bioactive fragment of ADNF (ADNF-9) can act at the level of the synapse to preserve membrane glutamate and glucose transporter activities, and mitochondrial function, following exposure of synapses to oxidative insults. Such localized signaling actions of neurotrophic factors may play important roles in modifying synaptic plasticity and suppressing potentially neurotoxic cascades.
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Materials and Methods |
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Synaptosomes were prepared from cerebral cortex of adult female SpragueDawley rats (250300 g) using methods described previously (Keller et al., 1997a; Begley et al., 1999
). Briefly, cerebral cortices were homogenized in a solution containing 0.32 M sucrose, 4 µg/ml pepstatin, 5 µg/ml aprotinin, 20 µg/ml trypsin inhibitor, 4 µg/ml leupeptin, 0.2 mM PMSF, 2 mM EDTA, 2 mM EGTA and 20 mM Hepes. The homogenate was centrifuged for 10 min at 300 g at 4°C, and the supernatant centrifuged for 10 min at 12 400 g at 4°C. The pellet was resuspended in homogenization buffer, recentrifuged at 20 250 g, and the pellet centrifuged through a sucrose gradient (7 ml 1.18 M sucrose, pH 8.5; 7 ml 1 M sucrose, pH 8.0; 7 ml 0.85 M sucrose, pH 8) at 87 275 g for 2 h. Synaptosomes in the 1 M sucrose/1.18 M sucrose interface were diluted in Locke's buffer (in mM: NaCl 154, KCl 5.6, CaCl2 2.3, MgCl2 1.0, NaHCO3 3.6, glucose 5, Hepes 5 mM; pH 7.2) for all experiments. Synaptosomal suspensions were aliquoted (100 µl) into 1.5 ml Eppendorf tubes and incubated in a CO2 incubator at 37°C during experimental treatments. Aß (Aß2535) was purchased from Bachem (lot no. B01200) and a 1 mM stock solution was prepared in sterile deionized water ~6 h prior to use. FeSO4 was prepared as a 10 mM stock in water immediately prior to use. Bafilomycin A1 and K252a were purchased from Calbiochem (La Jolla, CA).
Glutamate and Glucose Transport Assays
The methods for quantifying glutamate and glucose transport in synaptosomes have been described previously (Keller et al., 1997a). For the glutamate uptake assay, synaptosomes (200 µg/tube) were incubated for 7 min with [3H]glutamate (0.1 µCi/ml). The synaptosomes were then pelleted, washed three times in Locke's buffer, and lysed in 200 µl of solution of 1% SDS in PBS. The lysate was placed in scintillation vials containing Scintiverse and radioactivity was counted in a Packard 2500TR liquid scintillation counter. For the glucose uptake assay synaptosomes (200 µg/tube) were subjected to experimental treatments and then washed three times in glucose-free Locke's buffer and the assay was started by the addition of 1.5 µCi of [3H]2-deoxyglucose. Seven minutes later the assay was stopped by pelleting the synaptosomes, washing twice with glucose-free Locke's solution, and lysing the synaptosomes in 200 µl of a 1% SDS/PBS solution. The lysate was placed in scintillation vials containing Scintiverse and radioactivity was counted in a Packard 2500TR liquid scintillation counter. Results were expressed as c.p.m./mg protein. The rates of glucose and glutamate uptake by synaptosomes remained constant under basal conditions throughout the time course of experiments (up to 4 h). In such assays of glucose and glutamate transport there is often considerable inter-assay variability in terms of c.p.m. of synaptosome-associated radioactivity, whereas intra-assay variability is quite low. Because we always included control conditions within an experiment, the experimental values were compared directly to the control value within the experiment.
Assessments of Mitochondrial Function and Reactive Oxygen Species Levels
The dye rhodamine 123 (Molecular Probes) was used as a measure of mitochondrial function; uptake of rhodamine 123 has been shown to be related to mitochondrial transmembrane potential (Mattson et al., 1993c; Bindokas and Miller, 1995
; Kim et al., 1998
). Briefly, synaptosomes were incubated for 30 min in the presence of 10 µM of the dye and then were washed twice in Locke's buffer. Following washing, the synaptosomes were seeded into 35 mm glass-bottomed culture dishes and were allowed to settle on the glass surface during a 1015 min incubation. Fluorescence in synaptosomes was imaged using a confocal laser scanning microscope with excitation at 488 nm and emission at 510 nm, and the average pixel intensity in user-defined areas corresponding to synaptosomal aggregates was determined using Imagespace software (Molecular Dynamics). All images were coded and analyzed without knowledge of experimental treatment history of the synaptosomes. The dye dihydrorhodamine 123 (DHR) enters mitochondria and fluoresces when oxidized by ROS (principally peroxynitrite) to the positively charged rhodamine 123 derivative (Kooy et al., 1994
; Mattson et al., 1997
). Following experimental treatment, synaptosomes were loaded with 10 µM DHR 123 for 30 min, and were then washed twice with Locke's buffer. Fluorescence was quantified as described for synaptosomes stained with rhodamine 123.
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Results |
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Discussion |
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ADNF is released from astrocytes by a mechanism dependent upon neuronal activity (Brenneman et al., 1998b), and both bFGF (Pechan et al., 1992
) and NGF (Schwartz and Mishler, 1990
) are also produced by astrocytes. The expressions of NGF and trkA (Lee et al., 1998
), bFGF (Lin et al., 1997
) and bFGF receptors (Reilly and Kumari, 1996
) in astrocytes are greatly increased following traumatic and ischemic brain insults. Cell culture data show that astrocyte-derived bFGF can protect neurons against excitotoxic insults (Mattson and Rychlik, 1990
). Our data demonstrate actions of bFGF, ADNF-9 and bFGF in synaptic terminals (increased glutamate and glucose transport under conditions of oxidative stress) that would be expected to protect those compartments against excitotoxic damage. Because astrocytes are intimately associated with synaptic terminals (Vernadakis, 1996
), our data suggest the possibility that astrocyte-derived neurotrophic factors can exert local protective actions on neuronal synaptic terminals. While the present studies did not allow determination of the specific compartments in which glucose and glutamate transport were modulated by neurotrophic factors, it seems likely [based on previous studies of glucose and glutamate transport in cell culture and in vivo studies (Maher et al., 1994
; Schousboe et al., 1997
)], that the majority of glucose uptake is by neuronal terminals, whereas glutamate uptake occurs largely in astrocytes.
Previous studies of the neuroprotective and plasticity-modulating actions of neurotrophic factors have focused on signaling cascades that result in modulation of gene expression. Both bFGF and NGF activate cell surface receptors with intrinsic tyrosine kinase activity, and activation of these receptors is known to initiate kinase cascades that result in activation of transcription factors (Schlessinger and Ulrich, 1992). Studies of cultured neurons have provided evidence that bFGF and NGF can regulate the expression of a variety of potentially neuroprotective gene products including antioxidant enzymes (Mattson et al., 1995
), proteins involved in cellular calcium homeostasis (Mattson et al., 1993b
; Pappas and Parnavelas, 1997
) and Bcl-2 family members (Allsopp et al., 1995
). The present findings are novel and intriguing because, since synaptosomes lack nuclei, the protective effects of neurotrophic factors in this preparation cannot involve a transcriptiondependent mechanism. The signal transduction mechanisms that mediate the rapid transcription-independent effects of ADNF-9, bFGF and NGF on synaptic membrane transporter and mitochondrial functions remain to be elucidated, but are presumed to involve specific membrane receptors. Previous studies have established the presence of specific receptors for NGF (Figueiredo et al., 1995
) and bFGF (Masumura et al., 1996
) in cortical neurons in adult rats. Receptors for NGF (Henry et al., 1994
) and bFGF (Torriglia and Blanquet, 1994
) are present in synaptic terminals. Moreover, it was previously reported that treatment of synaptosomes with NGF results in enhancement of depolarization-induced neurotransmitter release (Sala et al., 1998
) and that NGF induces cAMP and IP3 production in synaptosomes (Knipper et al., 1993
). The synapto-protective actions of neurotrophic factors documented in the present study may therefore involve protein phosphorylation events similar to those that have recently been suggested to underlie the rapid modulation of synaptic plasticity by neurotrophic factors (Abe et al., 1992
). The ability of K252a to block the protective effects of NGF on synaptosomes is consistent with mediation by the high-affinity NGF receptor. Although the receptor(s) for ADNF remains to be identified, the responses of synaptosomes documented in the present study suggest that such receptors are present in synaptic terminals. A possible role for receptor-mediated endocytosis in the protective actions of ADNF is suggested by the ability of bafilomycin A1 to block such protective effects in synaptosomes. The specific compartments (presynaptic, postsynaptic and/or astrocytic) in which neurotrophic factors act to stimulate and preserve glucose and glutamate transport and mitochondrial function remain to be established.
Aß is believed to play a major role in promoting neuro-degenerative cascades in AD (Mattson, 1997). Impairment of glucose transport and mitochondrial function in cultured cortical and hippocampal neurons (Mark et al., 1997b
,c
), and of glutamate transport in cultured astrocytes (Blanc et al., 1998
), following exposure to Aß is mediated by increased levels of oxidative stress. Previous studies demonstrating adverse effects of Aß on glucose and glutamate transport in cortical synaptosomes also implicate oxidative stress in the underlying mechanism (Keller et al., 1997a
,b
). The present findings demonstrate that three different neurotrophic factors can protect synaptosomes against Aßand Fe2+-induced impairment of glucose and glutamate transport. Both Aß and Fe2+ induce membrane lipid peroxidation in neurons and synaptosomes, and this action of these insults appears to mediate impairment of the transporters because transporter functions are preserved in neurons and synaptosomes treated with antioxidants that suppress membrane lipid peroxidation (Mark et al., 1997a
,c
; Keller et al., 1997a
). A striking action of Aß on cultured hippocampal and cortical neurons is to increase their vulnerability to excitotoxicity (Koh et al., 1990
; Mattson et al., 1992
). Previous studies have shown that bFGF, NGF and ADNF can protect cultured hippocampal and cortical neurons against excitotoxic, metabolic and oxidative insults (Mattson et al., 1989
, 1993b
,c
; Zhang et al., 1993
; Brenneman et al., 1998a
,b
). Basic FGF (Mattson et al., 1993a
) and ADNF (Brenneman et al., 1998a
,b
) have also been reported to protect cultured hippocampal neurons against Aß toxicity. The present findings suggest the possibility that the neuroprotective mechanism of these trophic factors may be exerted at the level of the synapse. Synapse loss is a striking characteristic of AD (DeKosky et al., 1996
) and Aß and excessive activation of glutamate receptors may promote such synapse loss (Mattson et al., 1998a
,b
). Therefore, the possibility that enhancement of neurotrophic factor signaling in synaptic compartments may forestall the neurodegenerative process in AD and related disorders merits further investigation.
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Notes |
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Address correspondence to Mark P. Mattson, Laboratory of Neurosciences, National Institute of Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. Email: mattsonm{at}grc.nia.nih.gov.
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Footnotes |
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References |
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---|
Allsopp TE, Kiselev S, Wyatt S, Davies AM (1995) Role of Bcl-2 in the brain-derived neurotrophic factor survival response. Eur J Neurosci 7:12661272.[ISI][Medline]
Beal MF (1998) Mitochondrial dysfunction in neurodegenerative diseases. Biochim Biophys Acta 1366:211223.[ISI][Medline]
Begley JG, Duan W, Chan S, Duff K, Mattson MP (1999) Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. J Neurochem 72:10301039.[ISI][Medline]
Bindokas VP, Miller RJ (1995) Excitotoxic degeneration is initiated at non-random sites in cultured rat cerebellar neurons. J Neurosci 15:69997011.[Abstract]
Blanc EM, Keller JN, Fernandez S, Mattson MP (1998) 4-Hydroxynonenal, a lipid peroxidation product, inhibits glutamate transport in astrocytes. Glia 22:149160.[ISI][Medline]
Brenneman DE, Gozes I (1996) A femtomolar-acting neuroprotective peptide. J Clin Invest 97:22992307.
Brenneman DE, Hauser J, Neale E, Rubinraut S, Fridkin M, Davidson A, Gozes I (1998a) Activity-dependent neurotrophic factor: structure activity relationships of femtomolar-acting peptides. J Pharmacol Exp Ther 285:619627.
Brenneman DE, Glazner G, Hill JM, Hauser J, Davidson A, Gozes I (1998b) VIP neurotrophism in the central nervous system: multiple effectors and identification of a femtomolar-acting neuroprotective peptide. Ann NY Acad Sci 865:207212.
Cheng B, Mattson MP (1991) NGF and bFGF protect rat and human central neurons against hypoglycemic damage by stabilizing calcium homeostasis. Neuron 7:10311041.[ISI][Medline]
Cheng B, Christakos S, Mattson MP (1994) Tumor necrosis factors protect neurons against excitotoxic/metabolic insults and promote maintenance of calcium homeostasis. Neuron 12:139153.[ISI][Medline]
Cheng B, Furukawa K, O'Keefe JA, Goodman Y, Kihiko M, Fabian T, Mattson MP (1995) Basic fibroblast growth factor selectively increases AMPA-receptor subunit GluR1 protein level and differentially modulates Ca2+ responses to AMPA and NMDA in hippocampal neurons. J Neurochem 65:25252536.[ISI][Medline]
Choi DW (1994) Calcium and excitotoxic neuronal injury. Ann NY Acad Sci 747:162171.[ISI][Medline]
DeKosky ST, Scheff SW, Styren SD (1996) Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 5:417421.[ISI][Medline]
Denk W, Yuste R, Svoboda K, Tank DW (1996) Imaging calcium dynamics in dendritic spines. Curr Opin Neurobiol 6:372378.[ISI][Medline]
Figueiredo BC, Skup M, Bedard AM, Tetzlaff W, Cuello AC (1995) Differential expression of p140trk, p75NGFR and growth-associated phosphoprotein-43 genes in nucleus basalis magnocellularis, thalamus and adjacent cortex following neocortical infarction and nerve growth factor treatment. Neuroscience 68:2945.[ISI][Medline]
Guegan C, Onteniente B, Makiura Y, Merad-Boudia M, Ceballos-Picot I, Sola B (1998) Reduction of cortical infarction and impairment of apoptosis in NGF-transgenic mice subjected to permanent focal ischemia. Mo. Brain Res 55:133140.
Guo Q, Fu W, Sopher BL, Miller MW, Ware CB, Martin GM, Mattson MP (1999) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nature Med 5:101107.[ISI][Medline]
Henry MA, Westrum LE, Bothwell M, Press S (1994) Electron microscopic localization of nerve growth factor receptor (p75)-immunoreactivity in pars caudalis/medullary dorsal horn of the cat. Brain Res 642:137145.[ISI][Medline]
Jiang M, Lee CL, Smith KL, Swann JW (1998) Spine loss and other persistent alterations of hippocampal pyramidal cell dendrites in a model of early-onset epilepsy. J Neurosci 18:83568368.
Keller JN, Pang Z, Geddes JW, Begley JG, Germeyer A, Waeg G, Mattson MP (1997a) Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid ß-peptide: role of the lipid peroxidation product 4-hydroxynonenal. J Neurochem 69:273284.[ISI][Medline]
Keller JN, Mark RJ, Bruce AJ, Blanc EM, Rothstein JD, Uchida K, Mattson MP (1997b) 4-hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes. Neuroscience 80:685696.[ISI][Medline]
Keller JN, Kindy MS, Holtsberg FW, St Clair DK, Yen H-C, Germeyer A, Stiener SM, Bruce-Keller AJ, Hutchins JB, Mattson MP (1998) Mitochondrial MnSOD prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation and mitochondrial dysfunction. J Neurosci 18:687697.
Kelly A, Conroy S, Lynch MA (1998) Evidence that nerve growth factor plays a role in long-term potentiation in the rat dentate gyrus. Neuropharmacology 37:561570.[ISI][Medline]
Kim M, Cooper DD, Hayes SF, Spangrude GJ (1998) Rhodamine-123 staining in hematopoietic stem cells of young mice indicates mitochondrial activation rather than dye efflux. Blood 91:41064117.
Knipper M, Beck A, Rylett J, Breer H (1993) Neurotrophin induced second messenger responses in rat brain synaptosomes. NeuroReport 4:483486.[ISI][Medline]
Koh J, Yang LL, Cotman CW (1990) Beta-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res 533:315320.[ISI][Medline]
Kooy NW, Royall JA, Ischoropoulos H, Beckman JS (1994) Peroxynitritemediated oxidation of dihydrorhodamine 123. Free Radic Biol Med 16:149156.[ISI][Medline]
Lee TH, Kato H, Chen ST, Kogure K, Itoyama Y (1998) Expression of nerve growth factor and trkA after transient focal cerebral ischemia in rats. Stroke 29:16871696.
Lewin GR and Barde YA (1996) Physiology of the neurotrophins. Annu Rev Neurosci 19:289317.[ISI][Medline]
Lin TN, Te J, Lee M, Sun GY, Hsu CY (1997) Induction of basic fibroblast growth factor (bFGF) expression following focal cerebral ischemia. Mol Brain Res. 49:255265.[ISI][Medline]
Maher F, Vannucci SJ, Simpson IA (1994) Glucose transporter proteins in brain. FASEB J 8:10031011.
Mark RJ, Hensley K, Butterfield DA, Mattson MP (1995) Amyloid ß-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death. J Neurosci 15:62396249.[Abstract]
Mark RJ, Lovell MA, Markesbery WR, Uchida K, Mattson MP (1997a) A role for 4-hydroxynonenal in disruption of ion homeostasis and neuronal death induced by amyloid ß-peptide. J Neurochem 68:255264.[ISI][Medline]
Mark RJ, Keller JN, Kruman I, Mattson MP (1997b) Basic FGF attenuates amyloid ß-peptide-induced oxidative stress, mitochondrial dysfunction, and impairment of Na+/K+-ATPase activity in hippocampal neurons. Brain Res 756:205214.[ISI][Medline]
Mark RJ, Pang Z, Geddes JW, Uchida K, Mattson MP (1997c) Amyloid ß-peptide impairs glucose uptake in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J Neurosci 17:10461054.
Masumura M, Murayama N, Inoue T, Ohno T (1996) Selective induction of fibroblast growth factor receptor-1 mRNA after transient focal ischemia in the cerebral cortex of rats. Neurosci Lett 213:119122.[ISI][Medline]
Mattson MP (1997) Cellular actions of ß-amyloid precursor protein, and its soluble and fibrillogenic peptide derivatives. Physiol Rev 77: 10811132.
Mattson MP, Rychlik B (1990) Glia protect hippocampal neurons against excitatory amino acid-induced degeneration: involvement of fibroblast growth factor. Int J Dev Neurosci 8:399415.[ISI][Medline]
Mattson MP, Scheff SW (1994) Endogenous neuroprotection factors and traumatic brain injury: mechanisms of action and implications for therapies. J Neurotrauma 11:333.[ISI][Medline]
Mattson MP, Lindvall O (1997) Neurotrophic factor and cytokine signaling in the aging brain. In: The aging brain (Mattson MP, Geddes JW, eds), Adv Cell Aging Gerontol 2:299345.
Mattson MP, Murrain M, Guthrie PB, Kater SB (1989) Fibroblast growth factor and glutamate: opposing actions in the generation and degeneration of hippocampal neuroarchitecture. J Neurosci 9:37283740.[Abstract]
Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE (1992) ß-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12:376389.[Abstract]
Mattson MP, Tomaselli K, Rydel RE (1993a) Calcium-destabilizing and neurodegenerative effects of aggregated ß-amyloid peptide are attenuated by basic FGF. Brain Res 621:3549.[ISI][Medline]
Mattson MP, Kumar K, Cheng B, Wang H, Michaelis EK (1993b) Basic FGF regulates the expression of a functional 71 kDa NMDA receptor protein that mediates calcium influx and neurotoxicity in cultured hippocampal neurons. J Neurosci 13:45754588.[Abstract]
Mattson MP, Zhang Y, Bose S (1993c) Growth factors prevent mitochondrial dysfunction, loss of calcium homeostasis and cell injury, but not ATP depletion in hippocampal neurons deprived of glucose. Exp Neurol 121:113.[ISI][Medline]
Mattson MP, Lovell MA, Furukawa K, Markesbery WR (1995) Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of [Ca2+]i and neurotoxicity, and increase antioxidant enzyme activities in hippocampal neurons. J Neurochem 65:17401751.[ISI][Medline]
Mattson MP, Goodman Y, Luo H, Fu W, Furukawa K (1997) Activation of NF-B protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of Mn-SOD and suppression of peroxynitrite production and protein tyrosine nitration. J Neurosci Res 49:681697.[ISI][Medline]
Mattson MP, Keller JN, Begley JG (1998a) Evidence for synaptic apoptosis. Exp Neurol 153:3548.[ISI][Medline]
Mattson MP, Partin J, Begley JG (1998b) Amyloid ß-peptide induces apoptosis-related events in synapses and dendrites. Brain Res 807:167176.[ISI][Medline]
Mattson MP, Guo ZH, Geiger JD (1999) Secreted form of amyloid precursor protein enhances basal glucose and glutamate transport, and protects against oxidative impairment of glucose and glutamate transport in synaptosomes by a cyclic GMP-mediated mechanism. J Neurochem 73:532537.[ISI][Medline]
Nozaki K, Finklestein SP, Beal MF (1993) Basic fibroblast growth factor protects against hypoxia-ischemia and NMDA neurotoxicity in neonatal rats. J Cereb Blood Flow Metab 13:221228.[ISI][Medline]
Oppenheim RW (1991) Cell death during development of the nervous system. Annu Rev Neurosci 14:453501.[ISI][Medline]
Palmer AM, Robichaud PJ, Reiter CT (1994) The release and uptake of excitatory amino acids in rat brain: effect of aging and oxidative stress. Neurobiol Aging 15:103111.[ISI][Medline]
Pappas IS, Parnavelas JG (1997) Neurotrophins and basic fibroblast growth factor induce the differentiation of calbindin-containing neurons in the cerebral cortex. Exp Neurol 144:302314.[ISI][Medline]
Pechan PA, Chowdhury K, Seifert W (1992) Free radicals induce gene expression of NGF and bFGF in rat astrocyte culture. NeuroReport 3:469472.[ISI][Medline]
Peters A (1980) Morphological correlates of epilepsy: cells in the cerebral cortex. Adv Neurol 27:2148.[Medline]
Reilly JF, Kumari VG (1996) Alterations in fibroblast growth factor receptor expression following brain injury. Exp Neurol 140:139150.[ISI][Medline]
Rocamora N, Massieu L, Boddeke HW, Palacios JM, Mengod G (1994) Differential regulation of the expression of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNAs in adult rat brain after intrahippocampal injection of quinolinic acid. Mol Brain Res 26:8998.[ISI][Medline]
Rukenstein A, Rydel RE, Greene LA (1991) Multiple agents rescue PC12 cells from serum-free cell death by translationand transcriptionindependent mechanisms. J Neurosci 11:25522563.[Abstract]
Sala R, Viegi A, Rossi FM, Pizzorusso T, Bonanno G, Raiteri M, Maffei L (1998) Nerve growth factor and brain-derived neurotrophic factor increase neurotransmitter release in the rat visual cortex. Eur J Neurosci 10:21852191.[ISI][Medline]
Schlessinger J, Ulrich A (1992) Growth factor signaling by receptor tyrosine kinases. Neuron 9:383391.[ISI][Medline]
Schousboe A, Sonnewald U, Civenni G, Gegelashvili G (1997) Role of astrocytes in glutamate homeostasis. Implications for excitotoxicity. Adv Exp Med Biol 429:195206.[ISI][Medline]
Schwartz JP, Mishler K (1990) Beta-adrenergic receptor regulation, through cyclic AMP, of nerve growth factor expression in rat cortical and cerebellar astrocytes. Cell Mol Neurobiol 10:447457.[ISI][Medline]
Segal RA, Greenberg ME (1996) Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci 19:463489.[ISI][Medline]
Shigeno T, Mima T, Takakura K, Graham DI, Kato G, Hashimoto Y, Furukawa S (1991) Amelioration of delayed neuronal death in the hippocampus by nerve growth factor. J Neurosci 11:29142919.[Abstract]
Smith CD, Carney JM, Starke-Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA 88:1054010543.[Abstract]
Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, Tabaton M, Perry G (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70:22122215.[ISI][Medline]
Tanaka T, Saito H, Matsuki N (1996) Basic fibroblast growth factor modulates synaptic transmission in cultured rat hippocampal neurons. Brain Res 723:190195.[ISI][Medline]
Tancredi V, D'Arcangelo G, Mercanti D, Calissano P (1993) Nerve growth factor inhibits the expression of long-term potentiation in hippo-campal slices. NeuroReport 4:147150.[ISI][Medline]
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572580.[ISI][Medline]
Thoenen H (1995) Neurotrophins and neuronal plasticity. Science 270:593598.[Abstract]
Torriglia A, Blanquet PR (1994) Immunochemical evidence for a fibroblast growth factor receptor in adult retinal optic fiber and synaptic layers. Neuroscience 60:969981.[ISI][Medline]
Urban L, Neill KH, Crain BJ, Nadler JV, Somjen GG (1989) Postischemic synaptic physiology in area CA1 of the gerbil hippocampus studied in vitro. J Neurosci 9:39663975.[Abstract]
Van Der Wal EA, Gomez-Pinilla F, Cotman CW (1994) Seizure-associated induction of basic fibroblast growth factor and its receptor in the rat brain. Neuroscience 60:311323.[ISI][Medline]
Vernadakis A (1996) Glianeuron intercommunications and synaptic plasticity. Progr Neurobiol 49:185214.[ISI][Medline]
von Lubitz DK, Diemer NH (1983) Cerebral ischemia in the rat: ultrastructural and morphometric analysis of synapses in stratum radiatum of the hippocampal CA-1 region. Acta Neuropathol 61:5260.[ISI][Medline]
Zafra F, Hengerer B, Leibrock J, Thoenen H, Lindholm D (1990) Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J 9:35453550.[Abstract]
Zhang Y, Tatsuno T, Carney J, Mattson MP (1993) Basic FGF, NGF, and IGFs protect hippocampal neurons against iron-induced degeneration. J Cereb Blood Flow Metab 13:378388.[ISI][Medline]