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M P Mattson

Publications and source records attributed to M P Mattson.

At least 163 records · Page 9Linked to original sources
PubMed1998

Amyloid protein precursor stimulates excitatory amino acid transport. Implications for roles in neuroprotection and pathogenesis.

Excitatory neurotransmitters such as glutamate are required for the normal functioning of the central nervous system but can trigger excitotoxic neuronal injury if allowed to accumulate to abnormally high levels. Their extracellular levels are controlled primarily by transmitter uptake into astrocytes. Here, we demonstrate that the amyloid protein precursor may participate in the regulation of this important process. The amyloid protein precursor has been well conserved through evolution, and a number of studies indicate that it may function as an endogenous excitoprotectant. However, the mechanisms underlying this neuroprotective capacity remain largely unknown. At moderate levels of expression, human amyloid protein precursors increased glutamate/aspartate uptake in brains of transgenic mice, with the 751-amino acid isoform showing greater potency than the 695-amino acid isoform. Cerebral glutamate/aspartate transporter protein levels were higher in transgenic mice than in non-transgenic controls, whereas transporter mRNA levels were unchanged. Amyloid protein precursor-dependent stimulation of aspartate uptake by cultured primary astrocytes was associated with increases in protein kinase A and C activity and could be blocked by inhibitors of these kinases. The stimulation of astroglial excitatory amino acid transport by amyloid protein precursors could protect the brain against excitotoxicity and may play an important role in neurotransmission.

Amyloid beta-Protein Precursor↗
PubMed1998

Prevention of mitochondrial injury by manganese superoxide dismutase reveals a primary mechanism for alkaline-induced cell death.

Alkalosis is a clinical complication resulting from various pathological and physiological conditions. Although it is well established that reducing the cellular proton concentration is lethal, the mechanism leading to cell death is unknown. Mitochondrial respiration generates a proton gradient and superoxide radicals, suggesting a possible link between oxidative stress, mitochondrial integrity, and alkaline-induced cell death. Manganese superoxide dismutase removes superoxide radicals in mitochondria, and thus protects mitochondria from oxidative injury. Cells cultured under alkaline conditions were found to exhibit elevated levels of mitochondrial membrane potential, reactive oxygen species, and calcium which was accompanied by mitochondrial damage, DNA fragmentation, and cell death. Overexpression of manganese superoxide dismutase reduced the levels of intracellular reactive oxygen species and calcium, restored mitochondrial transmembrane potential, and prevented cell death. The results suggest that mitochondria are the primary target for alkaline-induced cell death and that free radical generation is an important and early event conveying cell death signals under alkaline conditions.

Animals↗
PubMed1998

Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function.

Mutations in the presenilin 1 (PS-1) gene account for many cases of early-onset autosomal dominant inherited forms of Alzheimer's disease. Recent findings suggest that PS-1 mutations may sensitize neurons to apoptosis induced by trophic factor withdrawal and exposure to amyloid beta-peptide (Abeta). We now report that overexpression of the calcium-binding protein calbindin D28k prevents apoptosis in cultured neural cells expressing mutant PS-1 (L286V and M146V missense mutations). Elevations of the intracellular Ca2+ concentration and generation of reactive oxygen species induced by Abeta, and potentiated by mutant PS-1, were suppressed in calbindin-overexpressing cells. Impairment of mitochondrial function by Abeta (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by calbindin. These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis, which leads to oxidative stress and mitochondrial dysfunction.

Amyloid beta-Peptides↗
PubMed1998

Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells.

The bacterial alkaloid staurosporine is widely employed as an inducer of apoptosis in many cell types including neurons. The intracellular cascades that mediate staurosporine-induced apoptosis are largely unknown. Exposure of cultured PC12 cells to staurosporine resulted in a rapid (min) and prolonged (1-6 hr) elevation of intracellular free calcium levels [Ca2+]i, accumulation of mitochondrial reactive oxygen species (ROS), and decreased mitochondrial 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction (1-4 hr). These early events were followed by membrane lipid peroxidation, loss of mitochondrial transmembrane potential, and nuclear apoptotic changes. Treatment of cells with serum or nerve growth factor within 1-2 hr of staurosporine exposure resulted in recovery of [Ca2+]i and ROS levels, and rescued the cells from apoptosis. The increased [Ca2+]i and ROS production were required for staurosporine-induced apoptosis because the intracellular calcium chelator BAPTA and uric acid (an agent that scavenges peroxynitrite) each protected cells against apoptosis. The caspase inhibitor zVAD-fmk and the anti-apoptotic gene product Bcl-2 prevented the sustained [Ca2+]i increase and ROS accumulation induced by staurosporine indicating that caspases act very early in the apoptotic process. Our data indicate that a [Ca2+]i increase is an early and critical event in staurosporine-induced apoptosis that engages a cell death pathway involving ROS production, oxidative stress, and mitochondrial dysfunction.

Animals↗
PubMed1998

Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction.

Oxidative stress is implicated in neuronal apoptosis that occurs in physiological settings and in neurodegenerative disorders. Superoxide anion radical, produced during mitochondrial respiration, is involved in the generation of several potentially damaging reactive oxygen species including peroxynitrite. To examine directly the role of superoxide and peroxynitrite in neuronal apoptosis, we generated neural cell lines and transgenic mice that overexpress human mitochondrial manganese superoxide dismutase (MnSOD). In cultured pheochromocytoma PC6 cells, overexpression of mitochondria-localized MnSOD prevented apoptosis induced by Fe2+, amyloid beta-peptide (Abeta), and nitric oxide-generating agents. Accumulations of peroxynitrite, nitrated proteins, and the membrane lipid peroxidation product 4-hydroxynonenal (HNE) after exposure to the apoptotic insults were markedly attenuated in cells expressing MnSOD. Glutathione peroxidase activity levels were increased in cells overexpressing MnSOD, suggesting a compensatory response to increased H2O2 levels. The peroxynitrite scavenger uric acid and the antioxidants propyl gallate and glutathione prevented apoptosis induced by each apoptotic insult, suggesting central roles for peroxynitrite and membrane lipid peroxidation in oxidative stress-induced apoptosis. Apoptotic insults decreased mitochondrial transmembrane potential and energy charge in control cells but not in cells overexpressing MnSOD, and cyclosporin A and caspase inhibitors protected cells against apoptosis, demonstrating roles for mitochondrial alterations and caspase activation in the apoptotic process. Membrane lipid peroxidation, protein nitration, and neuronal death after focal cerebral ischemia were significantly reduced in transgenic mice overexpressing human MnSOD. The data suggest that mitochondrial superoxide accumulation and consequent peroxynitrite production and mitochondrial dysfunction play pivotal roles in neuronal apoptosis induced by diverse insults in cell culture and in vivo.

Animals↗
PubMed1998

4-hydroxynonenal, a lipid peroxidation product, impairs glutamate transport in cortical astrocytes.

Astrocytes possess plasma membrane glutamate transporters that rapidly remove glutamate from the extracellular milieu and thereby prevent excitotoxic injury to neurons. Cellular oxidative stress is increased in neural tissues in a variety of acute and chronic neurodegenerative conditions. Recent findings suggest that oxidative stress increases neuronal vulnerability to excitotoxicity and that membrane lipid peroxidation plays a key role in this process. We now report that 4-hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, impairs glutamate transport in cultured cortical astrocytes. Impairment of glutamate transport occurred within 1-3 h of exposure to HNE; FeSO4, an inducer of membrane lipid peroxidation, also impaired glutamate transport. Vitamin E prevented impairment of glutamate transport induced by FeSO4, but not that induced by HNE, consistent with HNE acting as an effector of lipid peroxidation-induced impairment of glutamate transport. Glutathione, which binds and thereby detoxifies HNE, prevented HNE from impairing glutamate transport. Western blot, immunoprecipitation, and immunocytochemical analyses using an antibody against HNE-protein conjugates provided evidence that HNE covalently binds to many different astrocytic proteins including the glutamate transporter GLT-1. Data further suggest that HNE promotes intermolecular cross-linking of GLT-1 monomers to form dimers. HNE also induced mitochondrial dysfunction and accumulation of peroxides in astrocytes. Impairment of glutamate transport and mitochondrial function occurred with sublethal concentrations of HNE, concentrations known to be generated in cells exposed to various oxidative insults. Collectively, our data suggest that HNE may be an important mediator of oxidative stress-induced impairment of astrocytic glutamate transport and may thereby play a role in promoting neuronal excitotoxicity.

Aldehydes↗
PubMed1998

Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis.

A marker of lipid peroxidation 4-hydroxynonenal (HNE) was elevated in the cerebrospinal fluid (CSF) of a patient with sporadic amyotrophic lateral sclerosis (sALS) compared with that of most patients with other neurological diseases. Such elevations of HNE were sufficient to kill cyclic adenosine monophosphate (cAMP)-differentiated motor neuron hybrid cells in vitro, and anti-oxidants prevented this HNE-dependent cell death. These data suggest that oxidative stress and lipid peroxidation are associated with and may promote motor neuron degeneration in sALS.

Aldehydes↗
PubMed1998

Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients.

We report increased modification of proteins by 4-hydroxynonenal (HNE), a product of membrane lipid peroxidation, in the lumbar spinal cord of sporadic amyotrophic lateral sclerosis (ALS) patients versus that of neurologically normal controls. By immunohistochemistry, HNE-protein modification was detected in ventral horn motor neurons, and immunoprecipitation analysis revealed that one of the proteins modified by HNE was the astrocytic glutamate transporter EAAT2. Given that the function of proteins modified by HNE can be severely compromised as previously demonstrated for glutamate transporters in cortical synaptosome preparations, our findings suggest a scenario in which oxidative stress leads to the production of HNE, impairment of glutamate transport, and excitotoxic motor neuron degeneration in ALS.

Aged↗
PubMed1998

Evidence for synaptic apoptosis.

Increasing evidence indicates that neurons die by apoptosis, an active form of cell death involving a relatively stereotyped series of biochemical changes that culminate in nuclear fragmentation, in many different developmental and pathophysiological settings. In contrast to most other cell types, neurons have elaborate morphologies with complex neuritic arbors that often extend great distances from the cell body. Neuronal death signals are likely to be activated at remote synaptic sites and, indeed, overactivation of glutamate receptors and underactivation of trophic factor receptors are implicated in neurodegenerative disorders. We now report that biochemical changes consistent with apoptosis are engaged locally in synapses. Exposure of cortical synaptosomes to staurosporine and Fe2+ resulted in loss of membrane phospholipid asymmetry, caspase activation, and mitochondrial alterations (membrane depolarization, calcium overload, and oxyradical accumulation) characteristic of apoptosis. The caspase inhibitor zVAD-fmk prevented mitochondrial membrane depolarization in synaptosomes. Studies of the effects of cytosolic extracts from synaptosomes exposed to apoptotic insults, on isolated nuclei, showed that signals capable of inducing nuclear apoptosis are generated locally in synapses. Exposure of cultured hippocampal neurons to staurosporine and glutamate resulted in caspase activation and mitochondrial membrane depolarization in dendrites, and zVAD-fmk prevented the membrane depolarization. Glutamate-induced increases in caspase activity were first observed in dendrites and later in the cell body, and focal application of glutamate to individual dendrites resulted in local activation of caspases. Collectively, the data demonstrate that apoptotic biochemical cascades can be activated locally in synapses and dendrites and suggest a role for such local apoptotic signals in synapse loss and neuronal death in neurodegenerative disorders that involve excessive activation of glutamate receptors.

Animals↗
PubMed1998

HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress.

Patients infected with HIV-1 often exhibit cognitive deficits that are related to progressive neuronal degeneration and cell death. The protein Tat, which is released from HIV-1-infected cells, was recently shown to be toxic toward cultured neurons. We now report that Tat induces apoptosis in cultured embryonic rat hippocampal neurons. Tat induced caspase activation, and the caspase inhibitor zVAD-fmk prevented Tat-induced neuronal death. Tat induced a progressive elevation of cytoplasmic-free calcium levels, which was followed by mitochondrial calcium uptake and generation of mitochondrial-reactive oxygen species (ROS). The intracellular calcium chelator BAPTA-AM and the inhibitor of mitochondrial calcium uptake ruthenium red protected neurons against Tat-induced apoptosis. zVAD-fmk suppressed Tat-induced increases of cytoplasmic calcium levels and mitochondrial ROS accumulation, indicating roles for caspases in the perturbed calcium homeostasis and oxidative stress induced by Tat. An inhibitor of nitric oxide synthase, and the peroxynitrite scavenger uric acid, protected neurons against Tat-induced apoptosis, indicating requirements for nitric oxide production and peroxynitrite formation in the cell death process. Finally, Tat caused a delayed and progressive mitochondrial membrane depolarization, and cyclosporin A prevented Tat-induced apoptosis, suggesting an important role for mitochondrial membrane permeability transition in Tat-induced apoptosis. Collectively, our data demonstrate that Tat can induce neuronal apoptosis by a mechanism involving disruption of calcium homeostasis, caspase activation, and mitochondrial calcium uptake and ROS accumulation. Agents that interupt this apoptotic cascade may prove beneficial in preventing neuronal degeneration and associated dementia in AIDS patients.

AIDS Dementia Complex↗
PubMed1998

Catecholamines potentiate amyloid beta-peptide neurotoxicity: involvement of oxidative stress, mitochondrial dysfunction, and perturbed calcium homeostasis.

Oxidative stress and mitochondrial dysfunction are implicated in the neuronal cell death that occurs in physiological settings and in neurodegenerative disorders. In Alzheimer's disease (AD) degenerating neurons are associated with deposits of amyloid beta-peptide (A beta), and there is evidence for increased membrane lipid peroxidation and protein oxidation in the degenerating neurons. Cell culture studies have shown that A beta can disrupt calcium homeostasis and induce apoptosis in neurons by a mechanism involving oxidative stress. We now report that catecholamines (norepinephrine, epinephrine, and dopamine) increase the vulnerability of cultured hippocampal neurons to A beta toxicity. The catecholamines were effective in potentiating A beta toxicity at concentrations of 10-200 microM, with the higher concentrations (100-200 microM) themselves inducing cell death. Serotonin and acetylcholine were not neurotoxic and did not modify A beta toxicity. Levels of membrane lipid peroxidation, and cytoplasmic and mitochondrial reactive oxygen species, were increased following exposure to neurons to A beta, and catecholamines exacerbated the oxidative stress. Subtoxic concentrations of catecholamines exacerbated decreases in mitochondrial energy charge and transmembrane potential caused by A beta, and higher concentrations of catecholamines alone induced mitochondrial dysfunction. Antioxidants (vitamin E, glutathione, and propyl gallate) protected neurons against the damaging effects of A beta and catecholamines, whereas the beta-adrenergic receptor antagonist propanolol and the dopamine (D1) receptor antagonist SCH23390 were ineffective. Measurements of intracellular free Ca2+ ([Ca2+]i) showed that A beta induced a slow elevation of [Ca2+]i which was greatly enhanced in cultures cotreated with catecholamines. Collectively, these data indicate a role for catecholamines in exacerbating A beta-mediated neuronal degeneration in AD and, when taken together with previous findings, suggest roles for oxidative stress induced by catecholamines in several different neurodegenerative conditions.

Amyloid beta-Peptides↗
PubMed1998

Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity.

Oxyradicals attack double bonds of unsaturated fatty acids in cell membranes in a process called membrane lipid peroxidation (MLP).This process occurs in many different acute and chronic neurodegenerative conditions, and to a lesser extent during normal physiological activity in neuronal circuits. It can modify neurotransmitter release and uptake, ion-channel activity, the function of ion-motive ATPases and glucose transporters,and the coupling of cell-surface receptors to GTP-binding proteins. MLP can also impair mitochondrial function and promote a cascade of events that culminates in apoptotic cell death. The lipid peroxidation product 4-hydroxynonenal might play a central role in MLP-induced alterations in plasma membrane and mitochondrial protein functions. The modification of processes such as outgrowth of neurites and long-term potentiation of synaptic transmission by agents that suppress or promote MLP suggests roles for subtoxic levels of MLP in neuronal plasticity.

Adaptation, Physiological↗
PubMed1998

Secreted amyloid precursor protein alpha selectively suppresses N-methyl-D-aspartate currents in hippocampal neurons: involvement of cyclic GMP.

The secreted form of beta-amyloid precursor protein (sAPP alpha) is released from neurons in an activity-dependent manner; data suggest sAPP alpha may play roles in regulating neuronal excitability, plasticity, and survival. In cultured hippocampal neurons sAPP alpha can suppress elevation of [Ca2+]i induced by glutamate and can protect neurons against excitotoxicity. We now report whole-cell patch-clamp data from studies of cultured embryonic rat hippocampal neurons which demonstrate that sAPP alpha selectively suppresses N-methyl-D-aspartate currents without affecting currents induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate or kainate. sAPP alpha suppressed N-methyl-D-aspartate current rapidly and reversibly at concentrations of 0.011 nM. Suppression of N-methyl-D-aspartate current by sAPP alpha is apparently mediated by cyclic guanosine monophosphate because 8-bromo-cyclic guanosine monophosphate suppressed N-methyl-D-aspartate current in a manner similar to sAPP alpha, and two different inhibitors of cyclic guanosine monophosphate-dependent protein kinase prevented sAPP alpha-induced suppression of N-methyl-D-aspartate current. In addition, okadaic acid prevented suppression of N-methyl-D-aspartate-induced current suggesting the involvement of a protein phosphatase in modulation of N-methyl-D-aspartate current by sAPP alpha. These data identify a mechanism whereby sAPP alpha can modulate cellular responses to glutamate, and suggest important roles for sAPP alpha in the various physiological and pathophysiological processes in which N-methyl-D-aspartate receptors participate.

Amyloid beta-Protein Precursor↗
PubMed1998

Cryopreservation of rat cortical synaptosomes and analysis of glucose and glutamate transporter activities, and mitochondrial function.

Direct comparisons of synaptic functional parameters in brain tissues from different groups of experimental animals and different samples from post mortem human brain are often hindered by the inability to perform assays at the same time. To circumvent these difficulties we developed methods for cryopreservation and long-term storage of neocortical synaptosomes. The synaptosomes are suspended in a cryopreservation medium containing 10% dimethylsulfoxide and 10% fetal bovine serum, and are slowly cooled to -80 degreesC and then stored in liquid nitrogen. The function of plasma membrane glucose and glutamate transporters, and mitochondrial electron transport activity and membrane potential were measured in fresh, cryopreserved (CP), and non-cryopreserved freeze-thawed (NC) synaptosomes. Glucose and glutamate transporter activities, and mitochondrial functional parameters in CP synaptosomes were essentially identical to those in fresh unfrozen synaptosomes. Glucose and glutamate transport were severely compromised in NC synaptosomes, whereas mitochondrial function and cellular esterase activity were largely maintained. Electron paramagnetic resonance studies in conjunction with a protein-specific spin label indicated that cryopreservation did not alter the physical state of synaptosomal membrane proteins. These methods provide the opportunity to generate stocks of functional synaptosomes from different experiments or post mortem samples collected over large time intervals.

ATP-Binding Cassette Transporters↗
PubMed1998

Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease.

Prostate apoptosis response-4 (Par-4) is a protein containing both a leucine zipper and a death domain that was isolated by differential screening for genes upregulated in prostate cancer cells undergoing apoptosis. Par-4 is expressed in the nervous system, where its function is unknown. In Alzheimer disease (AD), neurons may die by apoptosis, and amyloid beta-protein (A beta) may play a role in this. We report here that Par-4 expression is increased in vulnerable neurons in AD brain and is induced in cultured neurons undergoing apoptosis. Blockade of Par-4 expression or function prevented neuronal apoptosis induced by Ab and trophic factor withdrawal. Par-4 expression was enhanced, and mitochondrial dysfunction and apoptosis exacerbated, in cells expressing presenilin-1 mutations associated with early-onset inherited AD.

Alzheimer Disease↗
PubMed1998

Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer's disease.

Many cases of autosomal dominant inherited forms of early-onset Alzheimer's disease are caused by mutations in the genes encoding presenilin-1 (PS-1; chromosome 14) and presenilin-2 (PS-2; chromosome 1). PSs are expressed in neurons throughout the brain wherein they appear to be localized primarily to the endoplasmic reticulum (ER) of cell bodies and dendrites. PS-1 and PS-2 show high homology and are predicted to have eight transmembrane domains with the C terminus, N terminus, and a loop domain all on the cytosolic side of the membrane; an enzymatic cleavage of PSs occurs at a site near the loop domain. The normal function of PSs is unknown, but data suggest roles in membrane trafficking, amyloid precursor protein processing, and regulation of ER calcium homeostasis. Homology of PSs to the C. elegans gene sel-12, which is involved in Notch signaling, and phenotypic similarities of PS-1 and Notch knockout mice suggest a developmental role for PSs in the nervous system. When expressed in cultured cells and transgenic mice, mutant PSs promote increased production of a long form of amyloid beta-peptide (A beta1-42) that may possess enhanced amyloidogenic and neurotoxic properties. PS mutations sensitize cultured neural cells to apoptosis induced by trophic factor withdrawal, metabolic insults, and amyloid beta-peptide. The mechanism responsible for the proapoptotic action of mutant PSs may involve perturbed calcium release from ER stores and increased levels of oxidative stress. Recent studies of apoptosis in many different cell types suggest that ER calcium signaling can modulate apoptosis. The evolving picture of PS roles in neuronal plasticity and Alzheimer's disease is bringing to the forefront the ER, an organelle increasingly recognized as a key regulator of neuronal plasticity and survival.

Alzheimer Disease↗
PubMed1998

Bcl-2 protects isolated plasma and mitochondrial membranes against lipid peroxidation induced by hydrogen peroxide and amyloid beta-peptide.

The bcl-2 protooncogene product possesses antiapoptotic properties in neuronal and nonneuronal cells. Recent data suggest that Bcl-2's potency as a survival factor hinges on its ability to suppress oxidative stress, but neither the subcellular site(s) nor the mechanism of its action is known. In this report electron paramagnetic resonance (EPR) spectroscopy analyses were used to investigate the local effects of Bcl-2 on membrane lipid peroxidation. Using hydrogen peroxide (H2O2) and amyloid beta-peptide (A beta) as lipoperoxidation initiators, we determined the loss of EPR-detectable paramagnetism of nitroxyl stearate (NS) spin labels 5-NS and 12-NS. In intact cell preparations and postnuclear membrane fractions, A beta and H2O2 induced significant loss of 5-NS and 12-NS signal amplitude in control PC12 cells, but not PC12 cells expressing Bcl-2. Cells were subjected to differential subcellular fractionation, yielding preparations of plasma membrane and mitochondria. In preparations derived from Bcl-2-expressing cells, both fractions contained Bcl-2 protein. 5-NS and 12-NS signals were significantly decreased following A beta and H2O2 exposure in control PC12 mitochondrial membranes, and Bcl-2 largely prevented these effects. Plasma membrane preparations containing Bcl-2 were also resistant to radical-induced loss of spin label. Collectively, our data suggest that Bcl-2 is localized to mitochondrial and plasma membranes where it can act locally to suppress oxidative damage induced by A beta and H2O2, further highlighting the important role of lipid peroxidation in apoptosis.

Amyloid beta-Peptides↗