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Biomedical subjects

M P Mattson

Publications and source records attributed to M P Mattson.

At least 73 records · Page 4Linked to original sources
PubMed2000

Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice.

Dysregulation of calcium signaling has been causally implicated in brain aging and Alzheimer's disease. Mutations in the presenilin genes (PS1, PS2), the leading cause of autosomal dominant familial Alzheimer's disease (FAD), cause highly specific alterations in intracellular calcium signaling pathways that may contribute to the neurodegenerative and pathological lesions of the disease. To elucidate the cellular mechanisms underlying these disturbances, we studied calcium signaling in fibroblasts isolated from mutant PS1 knockin mice. Mutant PS1 knockin cells exhibited a marked potentiation in the amplitude of calcium transients evoked by agonist stimulation. These cells also showed significant impairments in capacitative calcium entry (CCE, also known as store-operated calcium entry), an important cellular signaling pathway wherein depletion of intracellular calcium stores triggers influx of extracellular calcium into the cytosol. Notably, deficits in CCE were evident after agonist stimulation, but not if intracellular calcium stores were completely depleted with thapsigargin. Treatment with ionomycin and thapsigargin revealed that calcium levels within the ER were significantly increased in mutant PS1 knockin cells. Collectively, our findings suggest that the overfilling of calcium stores represents the fundamental cellular defect underlying the alterations in calcium signaling conferred by presenilin mutations.

Alzheimer Disease↗
PubMed2000

Caspase-mediated degradation of AMPA receptor subunits: a mechanism for preventing excitotoxic necrosis and ensuring apoptosis.

Activation of ionotropic glutamate receptors of the AMPA and NMDA subtypes likely contributes to neuronal injury and death in various neurodegenerative disorders. Excitotoxicity can manifest as either apoptosis or necrosis, but the mechanisms that determine the mode of cell death are not known. We now report that levels of AMPA receptor subunits GluR-1 and GluR-4 are rapidly decreased in cultured rat hippocampal neurons undergoing apoptosis in response to withdrawal of trophic support (WTS), whereas levels of NMDA receptor subunits NR1, NR2A, and NR2B are unchanged. Exposure of isolated synaptosomal membranes to "apoptotic" cytosolic extracts resulted in rapid degradation of AMPA receptor subunits. Treatment of cells and synaptosomal membranes with the caspase inhibitors prevented degradation of AMPA receptor subunits, demonstrating a requirement for caspases in the process. Calcium responses to AMPA receptor activation were reduced after withdrawal of trophic support and enhanced after treatment with caspase inhibitors. Vulnerability of neurons to excitotoxic necrosis was decreased after withdrawal of trophic support and potentiated by treatment with caspase inhibitors. Our data indicate that caspase-mediated degradation of AMPA receptor subunits occurs during early periods of cell stress and may serve to ensure apoptosis by preventing excitotoxic necrosis.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Presenilin-1 mutation increases neuronal vulnerability to focal ischemia in vivo and to hypoxia and glucose deprivation in cell culture: involvement of perturbed calcium homeostasis.

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Studies of cultured neural cells suggest that PS1 mutations result in perturbed cellular calcium homeostasis and may thereby render neurons vulnerable to apoptosis. In light of evidence that metabolic impairment plays a role in AD, that cerebral ischemia may be a risk factor for AD, and that individuals with AD have increased morbidity and mortality after stroke, we examined the impact of a PS1 mutation on neuronal vulnerability to ischemic injury. We report that the extent of brain injury after focal cerebral ischemia reperfusion is increased, and behavioral outcome is worsened, in PS1 mutant knock-in mice compared to wild-type mice. Cultured cortical neurons from PS1 mutant mice exhibit increased vulnerability to glucose deprivation and chemical hypoxia compared to their wild-type counterparts. Calcium imaging studies demonstrated enhanced elevation of intracellular calcium levels after glucose deprivation and chemical hypoxia in neurons from PS1 mutant mice. Agents that block calcium release from IP(3)- and ryanodine-sensitive stores (xestospongin and dantrolene, respectively) protected against the endangering action of the PS1 mutation. Our data suggest that presenilin mutations may promote neuronal degeneration in AD by increasing the sensitivity of neurons to age-related ischemia-like conditions. The data further suggest that drugs that stabilize endoplasmic reticulum calcium homeostasis may prove effective in suppressing the neurodegenerative process in AD patients.

Alzheimer Disease↗
PubMed2000

Concentration- and cell type-specific effects of calbindin D28k on vulnerability of hippocampal neurons to seizure-induced injury.

The calcium-binding protein calbindin D28k (CB) is expressed in limited subpopulations of neurons in the brain. In the hippocampus, CB is expressed in all dentate granule cells and a subpopulation of CA1 pyramidal neurons, but is absent from CA3 neurons. This pattern of CB expression is inversely correlated with neuronal vulnerability to seizure-induced damage suggesting the possibility that expression of CB confers resistance to excitotoxicity. While data from cell culture studies support an excitoprotective role for calbindin, it is not known whether CB is a key determinant of neuronal vulnerability in vivo. We therefore examined the pattern of damage to hippocampal neurons following intrahippocampal injection of the seizure-inducing excitotoxin kainate in CB homozygous (CB-/-) and CB heterozygous (CB+/-) knockout mice in comparison with wild-type mice (CB+/+). Whereas the extent of damage to CA1 neurons was similar in CB-/- and CB+/+ mice, damage to CA1 neurons was significantly reduced in CB+/- mice. Dentate granule neurons were not damaged following kainate-induced seizures in CB+/+, CB+/- or CB-/- mice. These findings suggest that CB can modify vulnerability of hippocampal CA1 neurons to seizure-induced injury, and that either CB is not a critical determinant of resistance of dentate granule neurons, or compensatory changes occur and lack of CB is not the only difference between CB-/- and CB+/+ mice.

Animals↗
PubMed2000

Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity.

The cytokine tumor necrosis factor-alpha (TNF), well-known for its roles in cellular responses to tissue injury, has recently been shown to be produced in response to physiological activity in neuronal circuits. TNF stimulates receptors in neurons linked to the activation of the transcription factor NF-kappaB, and recent findings suggest that this signaling pathway can modulate neuronal excitability and vulnerability of neurons to excitotoxicity. Because data indicate that TNF is produced, and NF-kappaB activated, under conditions associated with learning and memory, we performed experiments in the hippocampal slice preparation aimed at elucidating roles for TNF and NF-kappaB in modulating synaptic plasticity. Whereas stimulation of Schaffer collateral axons at a frequency of 1 Hz induced long-term depression (LTD) of synaptic transmission in region CA1 of wild-type mice, LTD did not occur in slices from TNF receptor knockout mice. Stimulation at 100 Hz induced long-term potentiation (LTP) in slices from both wild-type mice and mice lacking TNF receptors. Basal transmission was unaltered in mice lacking TNF receptors. Pretreatment of slices from wild-type mice with kappaB decoy DNA prevented induction of LTD and significantly reduced the magnitude of LTP. Collectively, these data suggest important roles for TNF and signaling pathways that modulate NF-kappaB activity in regulation of hippocampal synaptic plasticity.

Animals↗
PubMed2000

Differential effects of BDNF, ADNF9, and TNFalpha on levels of NMDA receptor subunits, calcium homeostasis, and neuronal vulnerability to excitotoxicity.

Calcium influx through N-methyl-d-aspartate (NMDA) receptors can result in neuronal apoptosis or necrosis and may play a pivotal role in neuronal death in many different neurodegenerative diseases. In the present study we employed primary neuronal cultures and three different excitoprotective factors, brain-derived neurotrophic factor (BDNF), activity-dependent neurotrophic factor (ADNF9), and tumor necrosis factor alpha (TNFalpha), to elucidate the mechanisms whereby trophic factors modify the excitotoxic process. Neurons pretreated with BDNF exhibited increased levels of the NMDA receptor subunits NR1 and NR2A, which was associated with increased calcium responses to NMDA and vulnerability to excitotoxic necrosis and reduced vulnerability to apoptosis. ADNF9 and TNFalpha suppressed calcium responses to glutamate and protected neurons against both excitotoxic necrosis and apoptosis, but had no effect on levels of NMDA receptor subunits. Inhibition of phosphorylation and DNA binding of NF-kappaB, by H7 and kappaB decoy DNA, respectively, suggest that the excitotoxic-modulating actions of BDNF are mediated by kinases, while those of ADNF9 and TNFalpha are mediated by both kinases and the transcription factor NF-kappaB. Our data show that, whereas BDNF increases neuronal responses to glutamate while ADNF9 and TNFalpha decrease the same, all three protect against excitotoxic apoptosis.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2000

Nicotine attenuates arachidonic acid-induced overexpression of nitric oxide synthase in cultured spinal cord neurons.

Primary spinal cord trauma can initiate a cascade of pathophysiologic events which markedly contribute to the expansion and amplification of the primary insult. The detailed mechanisms of these secondary neurochemical reactions are largely unknown; however, they involve membrane lipid derangements with the release of free fatty acids, in particular, arachidonic acid (AA). AA can induce several injury effects on spinal cord neurons. We hypothesize that upregulation of nitric oxide synthase (NOS) is among the most important mechanisms of arachidonic-acid-induced neuronal dysfunction and that nicotine can attenuate this effect. To study these hypotheses, spinal cord neurons were exposed to AA and/or nicotine, and several markers of neuronal nitric oxide synthase (nNOS) metabolism were measured. In addition, cotreatments with either inhibitors of nicotinic receptors or inhibitors of specific NOS isoforms were employed. Treatment with AA markedly increased activity of nNOS, as well as mRNA and protein levels of this enzyme. Changes in nNOS expression were accompanied by an increase in cellular cGMP and medium nitrite levels. Pretreatment with nicotine decreased AA-induced overexpression of nNOS and elevation of nitrite levels. In addition, it appeared that these nicotine effects could be partially modulated both by the alpha7 nicotinic receptors or by nonreceptor mechanisms. Alternatively, the observed changes could also be mediated by an alternate nicotinic receptor mechanism which is not blocked by alpha-bungarotoxin or mecamylamine. Results of the present study indicate that exposure to AA can lead to induction of nNOS in cultured spinal cord neurons. In addition, nicotine can exert a neuroprotective effect by attenuation of AA-induced upregulation of nNOS metabolism. These data may have therapeutic implications for the treatment of acute spinal cord trauma.

Animals↗
PubMed2000

Cyclosporin ameliorates traumatic brain-injury-induced alterations of hippocampal synaptic plasticity.

Although traumatic brain injury (TBI) often results in impaired learning and memory functions, the underlying mechanisms are unknown and there are currently no treatments that can preserve such functions. We studied plasticity at CA3-CA1 synapses in hippocampal slices from rats subjected to controlled cortical impact TBI. Long-term potentiation (LTP) of synaptic transmission was markedly impaired, whereas long-term depression (LTD) was enhanced, 48 h following TBI when compared to unoperated and sham control rats. Post-TBI administration of cyclosporin A, a compound that stabilizes mitochondrial function, resulted in a highly significant amelioration of the impairment of LTP and completely prevented the enhancement of LTD. Our data suggest that alterations in hippocampal synaptic plasticity may be responsible for learning and memory deficits resulting from TBI and that agents such as cyclosporin A that stabilize mitochondrial function may be effective treatments for TBI.

Action Potentials↗
PubMed2000

Basic fibroblast growth factor (bFGF) enhances functional recovery following severe spinal cord injury to the rat.

We have recently demonstrated that following a moderate contusion spinal cord injury (SCI) to rats, subsequent administration of basic fibroblast growth factor (bFGF) significantly enhances functional recovery and tissue sparing. To further characterize the effects of bFGF, we evaluated its efficacy after a more severe contusion injury at T(10) using the NYU impactor. Immediately after SCI, osmotic minipumps were implanted into the lateral ventricle and lumbar thecal sac to deliver bFGF at 3 or 6 microg per day versus control vehicle for 1 week. Animals were behaviorally tested for 6 weeks before histological assessment of tissue sparing through the injured segment and glial reactivity distal to the lesion. Compared to moderate SCI, all rats had more prolonged and sustained functional deficits 6 weeks after severe contusion. Subjects treated with bFGF had pronounced recovery of hindlimb movements from 2 to 6 weeks compared to controls, manifested in significantly higher behavioral scores. Only marginal tissue sparing was seen rostral to the injury in bFGF-treated spinal cords versus controls. Optical density measurements of astrocyte and microglial cell immunoreactivity in bFGF-treated spinal cords showed that after 6 weeks they approximated controls, although astrocyte immunoreactivity remained higher in controls rostrally. In summary, intrathecal infusion of bFGF following severe SCI significantly restores gross hindlimb motor function that is not correlated with significant tissue sparing. In light of previous evidence that pharmacological intervention with bFGF after moderate SCI enhances tissue preservation, the current findings indicate that yet undefined mechanisms contribute to the enhanced functional recovery following bFGF treatment.

Analysis of Variance↗
PubMed2000

Participation of par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by chorea, psychiatric disturbances, and dementia. It is caused by a polyglutamine repeat expansion in the huntingtin protein. The striatum is a major site of neuronal loss in HD, but the mechanisms underlying the neurodegenerative process have not been established. Systemic administration of the succinate dehydrogenase inhibitor 3-nitropropionic acid (3NP) to rodents results in motor dysfunction and degeneration of striatal neurons with features similar to those of HD. Here we report that levels of prostate apoptosis response-4 (Par-4; a protein recently linked to neuronal apoptosis) increase in striatum, and to a lesser extent in cortex and hippocampus, after systemic administration of 3NP to adult rats. The increase in Par-4 levels occurred within 6 h of 3NP administration and was followed by an increase in caspase activation which preceded neuronal loss. Exposure of cultured primary striatal neurons to 3NP induced a rapid increase of Par-4 levels and caspase activation. Treatment of striatal neurons with a Par-4 antisense oligonucleotide blocked Par-4 induction by 3NP, suppressed caspase activation, and attenuated neuronal apoptosis. The caspase-3 inhibitor DEVD suppressed 3NP-induced apoptosis of striatal neurons, but did not prevent induction of Par-4, indicating that Par-4 acts upstream of caspase-3 activation in the cell death pathway. Our results suggest that Par-4 plays an important role in the degeneration of striatal neurons in an experimental model of HD.

Animals↗
PubMed2000

In vivo 2-deoxyglucose administration preserves glucose and glutamate transport and mitochondrial function in cortical synaptic terminals after exposure to amyloid beta-peptide and iron: evidence for a stress response.

Mild metabolic stress can increase resistance of neurons in the brain to subsequent more severe insults, as exemplified by the beneficial effects of heat shock and ischemic preconditioning. Studies of Alzheimer's disease and other age-related neurodegenerative disorders indicate that dysfunction and degeneration of synapses occur early in the cell death process, and that oxidative stress and mitochondrial dysfunction are central events in this pathological process. It was recently shown that administration of 2-deoxy-d-glucose (2DG), a nonmetabolizable glucose analog that induces metabolic stress, to rats and mice can increase resistance of neurons in the brain to excitotoxic, ischemic, and oxidative injury. We now report that administration of 2DG to adult rats (daily i.p. injections of 100 mg/kg body weight) increases resistance of synaptic terminals to dysfunction and degeneration induced by amyloid beta-peptide and ferrous iron, an oxidative insult. The magnitude of impairment of glucose and glutamate transport induced by amyloid beta-peptide and iron was significantly reduced in cortical synaptosomes from 2DG-treated rats compared to saline-treated control rats. Mitochondrial dysfunction, as indicated by increased levels of reactive oxygen species and decreased transmembrane potential, was significantly attenuated after exposure to amyloid beta-peptide and iron in synaptosomes from 2DG-treated rats. Levels of the stress proteins HSP-70 and GRP-78 were increased in synaptosomes from 2DG-treated rats, suggesting a mechanism whereby 2DG protects synaptic terminals. We conclude that 2DG bolsters cytoprotective mechanisms within synaptic terminals, suggesting novel preventative and therapeutic approaches for neurodegenerative disorders.

ATP-Binding Cassette Transporters↗
PubMed2000

Dietary restriction selectively decreases glucocorticoid receptor expression in the hippocampus and cerebral cortex of rats.

Dietary restriction (DR) can extend life span and reduce the incidence of age-related disease in rodents and primates. DR can be considered as a metabolic stress and might therefore be expected to modify neuroendocrine systems that regulate stress responses. We now report that maintenance of adult rats on a DR regimen results in a significant decrease in the levels of glucocorticoid receptor mRNA and protein in the hippocampus and cerebral cortex, without a change in levels of mineralocorticoid receptors. These findings suggest that DR can alter the responsiveness of brain cells to glucocorticoids, an adaptation that may contribute to beneficial effects of DR on neuronal plasticity and survival demonstrated in recent studies.

Aging↗
PubMed2000

Apoptotic and antiapoptotic mechanisms in stroke.

Apoptosis is a form of programmed cell death that occurs in neurons during development of the nervous system and may also be a prominent form of neuronal death in chronic neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Recent findings also implicate apoptosis in neuronal degeneration after ischemic brain injury in animal models of stroke. Activation of both apoptotic and antiapoptotic signaling cascades occurs in neurons in animal and cell culture models of stroke. Apoptotic cascades involve: increased levels of intracellular oxyradicals and calcium; induction of expression of proteins such as Par-4 (prostate apoptosis response-4), which act by promoting mitochondrial dysfunction and suppressing antiapoptotic mechanisms; mitochondrial membrane depolarization, calcium uptake, and release of factors (e.g., cytochrome c) that ultimately induce nuclear DNA condensation and fragmentation; activation of cysteine proteases of the caspase family; activation of transcription factors such as AP-1 that may induce expression of "killer genes." Antiapoptotic signaling pathways are activated by neurotrophic factors, certain cytokines, and increases in oxidative and metabolic stress. Such protective pathways include: activation of the transcription factors (e.g., nuclear factor-kappa B, NF-kappa B) that induce expression of stress proteins, antioxidant enzymes, and calcium-regulating proteins; phosphorylation-mediated modulation of ion channels and membrane transporters; cytoskeletal alterations that modulate calcium homeostasis; and modulation of proteins that stabilize mitochondrial function (e.g., Bcl-2). Intervention studies in experimental stroke models have identified a battery of approaches of potential benefit in reducing neuronal death in stroke patients, including administration of antioxidants, calcium-stabilizing agents, caspase inhibitors, and agents that activate NF-kappa B. Interestingly, recent studies suggest novel dietary approaches (e.g., food restriction and supplementation with antioxidants) that may reduce brain damage following stroke.

Animals↗
PubMed2000

Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders.

Endoplasmic reticulum (ER) is a multifaceted organelle that regulates protein synthesis and trafficking, cellular responses to stress, and intracellular Ca2+ levels. In neurons, it is distributed between the cellular compartments that regulate plasticity and survival, which include axons, dendrites, growth cones and synaptic terminals. Intriguing communication networks between ER, mitochondria and plasma membrane are being revealed that provide mechanisms for the precise regulation of temporal and spatial aspects of Ca2+ signaling. Alterations in Ca2+ homeostasis in ER contribute to neuronal apoptosis and excitotoxicity, and are being linked to the pathogenesis of several different neurodegenerative disorders, including Alzheimer's disease and stroke.

Animals↗
PubMed2000

Emerging neuroprotective strategies for Alzheimer's disease: dietary restriction, telomerase activation, and stem cell therapy.

The molecular, biochemical and cellular events that result in synaptic dysfunction and neuronal degeneration in the brain in Alzheimer's disease (AD) are becoming known. Age-related increases in cellular oxidative stress, and impairment of energy metabolism, result in disruption of neuronal calcium homeostasis and increased vulnerability of neurons to excitotoxicity and apoptosis. Inherited forms of AD that result from mutations in the beta-amyloid precursor protein (APP) and presenilins accelerate the neurodegenerative cascade by increasing production and deposition of neurotoxic forms of amyloid beta-peptide and by perturbing calcium homeostasis. Dietary restriction (DR; reduced calorie intake with maintained nutrition) extends life span of rodents and (probably) humans. DR increases resistance of neurons to dysfunction and degeneration, and improves behavioral outcome, in experimental models of AD and other age-related neurodegenerative disorders by a mechanism involving a mild stress response. Telomerase, a specialized reverse transcriptase, has been proposed to possess anti-aging properties. The catalytic subunit of telomerase (TERT) is expressed in neurons throughout the brain during development, but is absent from neurons in the adult brain. TERT exhibits neuroprotective properties in experimental models of neurodegenerative disorders suggesting that manipulations that induce telomerase in neurons may protect against age-related neurodegeneration. Finally, the exciting and exploding field of stem cell research suggests methods for replacing damaged or lost brain cells in an array of neurological disorders.

Alzheimer Disease↗
PubMed2000

Apoptosis in neurodegenerative disorders.

Neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke, and amyotrophic lateral sclerosis. The identification of specific genetic and environmental factors responsible for these diseases has bolstered evidence for a shared pathway of neuronal death--apoptosis--involving oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases. These death cascades are counteracted by survival signals, which suppress oxyradicals and stabilize calcium homeostasis and mitochondrial function. With the identification of mechanisms that either promote or prevent neuronal apoptosis come new approaches for preventing and treating neurodegenerative disorders.

Animals↗