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Biomedical subjects

Mark P Mattson

Publications and source records attributed to Mark P Mattson.

At least 91 records · Page 5Linked to original sources
PubMed2004

Cellular lifespan and senescence signaling in embryonic stem cells.

Most mammalian cells when placed in culture will undergo a limited number of cell divisions before entering an unresponsive non-proliferating state termed senescence. However, several pathways that are activated singly or in concert can allow cells to bypass senescence at least for limited periods. These include the telomerase pathway required to maintain telomere ends, the p53 and Rb pathways required to direct senescence in response to DNA damage, telomere shortening and mitogenic signals, and the insulin-like growth factor--Akt pathway that may regulate lifespan and cell proliferation. In this review, we summarize recent findings related to these pathways in embryonic stem (ES) cells and suggest that ES cells are immortal because these pathways are tightly regulated.

Cellular Senescence↗
PubMed2004

Dietary supplementation with 2-deoxy-D-glucose improves cardiovascular and neuroendocrine stress adaptation in rats.

Dietary restriction and physical exercise can enhance stress resistance and reduce the risk of cardiovascular disease. We investigated the effects of dietary supplementation with 2-deoxy-d-glucose (2-DG), a glucose analog that limits glucose availability at the cellular level, on cardiovascular and neuroendocrine responses to stress in rats. Young adult male Sprague-Dawley rats were implanted with telemetry probes to monitor blood pressure (BP), heart rate, body temperature, and body movements. These variables were measured at designated times during a 6-mo period in rats fed control and 2-DG-supplemented (0.4% 2-DG, fed ad libitum on a schedule of 2 days on the diet and 1 day off the diet) diets during unperturbed conditions and during and after immobilization stress or cold-water swim stress. Rats fed the 2-DG diet exhibited significant reductions in resting BP, attenuated BP responses during stress, and accelerated recovery to baseline after stress. Plasma concentrations of ACTH and corticosterone were elevated under nonstress conditions in rats fed the 2-DG diet and exhibited differential responses to single (enhanced response) and multiple (reduced response) stress sessions compared with rats fed control rat chow ad libitum. The 2-DG diet improved glucose metabolism, as indicated by decreased concentrations of blood glucose and insulin under nonstress conditions, but glucose and insulin responses to stress were maintained. We conclude that improvements in some cardiovascular risk factors and stress adaptation in rats maintained on a 2-DG-supplemented diet are associated with reduced neuroendocrine responses to the stressors.

Adaptation, Physiological↗
PubMed2004

Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative disorders.

Membrane lipid peroxidation and oxidative modification of various membrane and associated proteins (e.g., receptors, ion transporters and channels, and signal transduction and cytoskeletal proteins) occur in a range of neurodegenerative disorders. This membrane-associated oxidative stress (MAOS) is promoted by redox-active metals, most notably iron and copper. The mechanisms whereby different genetic and environmental factors initiate MAOS in specific neurological disorders are being elucidated. In Alzheimer's disease (AD), the amyloid beta-peptide generates reactive oxygen species and induces MAOS, resulting in disruption of cellular calcium homeostasis. In Parkinson's disease (PD), mitochondrial toxins and perturbed ubiquitin-dependent proteolysis may impair ATP production and increase oxyradical production and MAOS. The inheritance of polyglutamine-expanded huntingtin may promote neuronal degeneration in Huntington's disease (HD), in part, by increasing MAOS. Increased MAOS occurs in amyotrophic lateral sclerosis (ALS) as the result of genetic abnormalities (e.g., Cu/Zn-superoxide dismutase mutations) or exposure to environmental toxins. Levels of iron are increased in vulnerable neuronal populations in AD and PD, and dietary and pharmacological manipulations of iron and copper modify the course of the disease in mouse models of AD and PD in ways that suggest a role for these metals in disease pathogenesis. An increasing number of pharmacological and dietary interventions are being identified that can suppress MAOS and neuronal damage and improve functional outcome in animal models of AD, PD, HD, and ALS. Novel preventative and therapeutic approaches for neurodegenerative disorders are emerging from basic research on the molecular and cellular actions of metals and MAOS in neural cells.

Alzheimer Disease↗
PubMed2004

New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists.

Owing to improving preventative, diagnostic, and therapeutic measures for cardiovascular disease and a variety of cancers, the average ages of North Americans and Europeans continue to rise. Regrettably, accompanying this increase in life span, there has been an increase in the number of individuals afflicted with age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and stroke. Although different cell types and brain areas are vulnerable among these, each disorder likely develops from activation of a common final cascade of biochemical and cellular events that eventually lead to neuronal dysfunction and death. In this regard, different triggers, including oxidative damage to DNA, the overactivation of glutamate receptors, and disruption of cellular calcium homeostasis, albeit initiated by different genetic and/or environmental factors, can instigate a cascade of intracellular events that induce apoptosis. To forestall the neurodegenerative process, we have chosen specific targets to inhibit that are at pivotal rate-limiting steps within the pathological cascade. Such targets include TNF-alpha, p53, and GLP-1 receptor. The cytokine TNF-alpha is elevated in Alzheimer's disease, Parkinson's disease, stroke, and amyotrophic lateral sclerosis. Its synthesis can be reduced via posttranscriptional mechanisms with novel analogues of the classic drug, thalidomide. The intracellular protein and transcription factor, p53, is activated by the Alzheimer's disease toxic peptide, Abeta, as well as by excess glutamate and hypoxia to trigger neural cell death. It is inactivated by novel tetrahydrobenzothiazole and -oxazole analogues to rescue cells from lethal insults. Stimulation of the glucagon-like peptide-1 receptor (GLP-1R) in brain is associated with neurotrophic functions that, additionally, can protect cells against excess glutamate and other toxic insults.

Animals↗
PubMed2004

Bone marrow transplantation reveals roles for brain macrophage/microglia TNF signaling and nitric oxide production in excitotoxic neuronal death.

The signaling mechanisms by which brain macrophages and microglia (BMM) respond to injury and disease, and how their responses affect neurodegenerative processes are largely unknown. Here we show that bone marrow transplantation can be used to introduce genetically modified BMM into the adult mouse brain to reveal the functions of one or more BMM genes in neuronal injury responses. Mice in which endogenous BMM were replaced with cells from mice lacking p55 and p75 tumor necrosis factor (TNF) receptors exhibit increased vulnerability of hippocampal neurons to excitotoxic injury suggesting a role for TNF signaling in BMM in the excitotoxic injury response. Neurons in the brains of mice with BMM lacking nitric oxide synthase exhibit reduced protein nitration and are less vulnerable to excitotoxic damage, indicating a pivotal role for BMM nitric oxide production in excitotoxic neuronal damage.

Animals↗
PubMed2004

Prophylactic activation of neuroprotective stress response pathways by dietary and behavioral manipulations.

It is well established that when most types of cells, including neurons, are exposed to a mild stress they increase their ability to resist more severe stress. This "preconditioning" phenomenon involves up-regulation of genes that encode cytoprotective proteins such as heat-shock proteins and growth factors. We found that a similar beneficial cellular stress response can be induced in neurons throughout the brain by a "meal-skipping" dietary restriction (DR) regimen in rats and mice. DR is effective in protecting neurons and improving functional outcome in models of stroke, Alzheimer's, Parkinson's and Huntington's diseases. DR induces an increase in the levels of brain-derived neurotrophic factor (BDNF) and heat-shock proteins in neurons. DR also stimulates neurogenesis in the hippocampus, and BDNF plays a role in this effect of DR. Physical exercise and environmental enrichment are two other manipulations that have been shown to induce BDNF expression in the brain, presumably because it is a mild cellular stress. When taken together with epidemiological and clinical studies in humans, the data from animal studies suggest that it may be possible to reduce the risk for age-related neurodegenerative disorders through dietary and behavioral modifications that act by promoting neuronal plasticity and survival.

Alzheimer Disease↗
PubMed2003

Reciprocal inhibition of p53 and nuclear factor-kappaB transcriptional activities determines cell survival or death in neurons.

The tumor suppressor and transcription factor p53 is a key modulator of cellular stress responses, and activation of p53 precedes apoptosis in many cell types. Controversial reports exist on the role of the transcription factor nuclear factor-kappaB (NF-kappaB) in p53-mediated apoptosis, depending on the cell type and experimental conditions. Therefore, we sought to elucidate the role of NF-kappaB in p53-mediated neuron death. In cultured neurons DNA damaging compounds induced activation of p53, whereas NF-kappaB activity declined significantly. The p53 inhibitor pifithrin-alpha (PFT) preserved NF-kappaB activity and protected neurons against apoptosis. Immunoprecipitation experiments revealed enhanced p53 binding to the transcriptional cofactor p300 after induction of DNA damage, whereas binding of p300 to NF-kappaB was reduced. In contrast, PFT blocked the interaction of p53 with the cofactor, whereas NF-kappaB binding to p300 was enhanced. Most interestingly, similar results were observed after oxygen glucose deprivation in cultured neurons and in ischemic brain tissue. Ischemia-induced repression of NF-kappaB activity was prevented and brain damage was reduced by the p53 inhibitor PFT in a dose-dependent manner. It is concluded that a balanced competitive interaction of p53 and NF-kappaB with the transcriptional cofactor p300 exists in neurons. Exposure of neurons to lethal stress activates p53 and disrupts NF-kappaB binding to p300, thereby blocking NF-kappaB-mediated survival signaling. Inhibitors of p53 provide pronounced neuroprotective effects because they block p53-mediated induction of cell death and concomitantly enhance NF-kappaB-induced survival signaling.

Acetyltransferases↗
PubMed2003

Gene-diet interactions in brain aging and neurodegenerative disorders.

While there are many examples of people who live for 100 years or more with little evidence of a decline in brain function, many others are not so fortunate and experience a neurodegenerative disorder, such as Alzheimer disease or Parkinson disease. Although an increasing number of genetic factors that may affect the risk for neurodegenerative disorders are being identified, emerging findings suggest that dietary factors play major roles in determining whether the brain ages successfully or experiences a neurodegenerative disorder. Dietary factors may interact with disease-causing or predisposing genes in molecular cascades that either promote or prevent the degeneration of neurons. Epidemiologic findings suggest that high-calorie diets and folic acid deficiency increase the risk for Alzheimer disease and Parkinson disease; studies of animal models of these disorders have shown that dietary restriction (reduced calorie intake or intermittent fasting) and dietary supplementation with folic acid can reduce neuronal damage and improve behavioral outcome. Animal studies have shown that the beneficial effects of dietary restriction on the brain result in part from increased production of neurotrophic factors and cytoprotective protein chaperones in neurons. By keeping homocysteine levels low, folic acid can protect cerebral vessels and prevent the accumulation of DNA damage in neurons caused by oxidative stress and facilitated by homocysteine. Although additional studies are required in humans, the emerging data suggest that high-calorie diets and elevated homocysteine levels may render the brain vulnerable to age-related neurodegenerative disorders, particularly in persons with a genetic predisposition to such disorders.

Aging↗
PubMed2003

Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction.

The neuropathological correlates of Alzheimer's disease (AD) include amyloid-beta (Abeta) plaques and neurofibrillary tangles. To study the interaction between Abeta and tau and their effect on synaptic function, we derived a triple-transgenic model (3xTg-AD) harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1(M146V) knockin mice, generating mice with the same genetic background. 3xTg-AD mice progressively develop plaques and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal Abeta. These studies suggest a novel pathogenic role for intraneuronal Abeta with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.

Alzheimer Disease↗
PubMed2003

Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain.

Nitric oxide (NO) is believed to act as an intercellular signal that regulates synaptic plasticity in mature neurons. We now report that NO also regulates the proliferation and differentiation of mouse brain neural progenitor cells (NPCs). Treatment of dissociated mouse cortical neuroepithelial cluster cell cultures with the NO synthase inhibitor L-NAME or the NO scavenger hemoglobin increased cell proliferation and decreased differentiation of the NPCs into neurons, whereas the NO donor sodium nitroprusside inhibited NPC proliferation and increased neuronal differentiation. Brain-derived neurotrophic factor (BDNF) reduced NPC proliferation and increased the expression of neuronal NO synthase (nNOS) in differentiating neurons. The stimulatory effect of BDNF on neuronal differentation of NPC was blocked by L-NAME and hemoglobin, suggesting that NO produced by the latter cells inhibited proliferation and induced neuronal differentiation of neighboring NPCs. A similar role for NO in regulating the switch of neural stem cells from proliferation to differentiation in the adult brain is suggested by data showing that NO synthase inhibition enhances NPC proliferation and inhibits neuronal differentiation in the subventricular zone of adult mice. These findings identify NO as a paracrine messenger stimulated by neurotrophin signaling in newly generated neurons to control the proliferation and differentiation of NPC, a novel mechanism for the regulation of developmental and adult neurogenesis.

Animals↗
PubMed2003

Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron.

Glucagon-like peptide-1(7-36)-amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the gastrointestinal tract in response to food. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. GLP-1 receptors, which are coupled to the cyclic AMP second messenger pathway, are expressed throughout the brains of rodents and humans. It was recently reported that GLP-1 and exendin-4, a naturally occurring, more stable analogue of GLP-1 that binds at the GLP-1 receptor, possess neurotrophic properties and can protect neurons against glutamate-induced apoptosis. We report here that GLP-1 can reduce the levels of amyloid-beta peptide (Abeta) in the brain in vivo and can reduce levels of amyloid precursor protein (APP) in cultured neuronal cells. Moreover, GLP-1 and exendin-4 protect cultured hippocampal neurons against death induced by Abeta and iron, an oxidative insult. Collectively, these data suggest that GLP-1 can modify APP processing and protect against oxidative injury, two actions that suggest a novel therapeutic target for intervention in Alzheimer's disease.

Alzheimer Disease↗
PubMed2003

Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport.

Several lines of evidence indicate that alterations in axonal transport play a critical role in Alzheimer's disease (AD) neuropathology, but the molecular mechanisms that control this process are not understood fully. Recent work indicates that presenilin 1 (PS1) interacts with glycogen synthase kinase 3beta (GSK3beta). In vivo, GSK3beta phosphorylates kinesin light chains (KLC) and causes the release of kinesin-I from membrane-bound organelles (MBOs), leading to a reduction in kinesin-I driven motility (Morfini et al., 2002b). To characterize a potential role for PS1 in the regulation of kinesin-based axonal transport, we used PS1-/- and PS1 knock-inM146V (KIM146V) mice and cultured cells. We show that relative levels of GSK3beta activity were increased in cells either in the presence of mutant PS1 or in the absence of PS1 (PS1-/-). Concomitant with increased GSK3beta activity, relative levels of KLC phosphorylation were increased, and the amount of kinesin-I bound to MBOs was reduced. Consistent with a deficit in kinesin-I-mediated fast axonal transport, densities of synaptophysin- and syntaxin-I-containing vesicles and mitochondria were reduced in neuritic processes of KIM146V hippocampal neurons. Similarly, we found reduced levels of PS1, amyloid precursor protein, and synaptophysin in sciatic nerves of KIM146V mice. Thus PS1 appears to modulate GSK3beta activity and the release of kinesin-I from MBOs at sites of vesicle delivery and membrane insertion. These findings suggest that mutations in PS1 may compromise neuronal function by affecting GSK-3 activity and kinesin-I-based motility.

Alzheimer Disease↗
PubMed2003

Mitochondrial potassium channels and uncoupling proteins in synaptic plasticity and neuronal cell death.

The function of the nervous system relies upon synaptic transmission, a process in which a neurotransmitter released from pre-synaptic terminals of one neuron (in response to membrane depolarization and calcium influx) activates post-synaptic receptors on dendrites of another neuron. Synapses are subjected to repeated bouts of oxidative and metabolic stress as the result of changing ion gradients and ATP usage. Mitochondria play central roles in meeting the demands of synapses for ATP and in regulating calcium homeostasis, and mitochondrial dysfunction can cause dysfunction and degeneration of synapses, and can trigger cell death. We have identified two types of mitochondrial proteins that serve the function of protecting synapses and neurons against dysfunction and death. Mitochondrial ATP-sensitive potassium (MitoKATP) channels modulate inner membrane potential and oxyradical production; mitochondrial potassium fluxes can affect cytochrome c release and caspase activation and may determine whether neurons live or die in experimental models of stroke and Alzheimer's disease. Uncoupling proteins (UCPs) are a family of mitochondrial membrane proteins that uncouple electron transport from ATP production by transporting protons across the inner membrane. Neurons express at least three UCPs including the widely expressed UCP-2 and the neuron-specific UCP-4 and UCP-5 (BMCP-1). We have found that UCP-4 protects neurons against apoptosis by a mechanism involving suppression of oxyradical production and stabilization of cellular calcium homeostasis. The expression of UCP-4 is itself regulated by changes in energy metabolism. In addition to their roles in neuronal cell survival and death, MitoKATP channels and UCPs may play roles in regulating neuronal differentiation during development and synaptic plasticity in the adult.

Apoptosis↗
PubMed2003

Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake.

Dietary restriction has been shown to have several health benefits including increased insulin sensitivity, stress resistance, reduced morbidity, and increased life span. The mechanism remains unknown, but the need for a long-term reduction in caloric intake to achieve these benefits has been assumed. We report that when C57BL6 mice are maintained on an intermittent fasting (alternate-day fasting) dietary-restriction regimen their overall food intake is not decreased and their body weight is maintained. Nevertheless, intermittent fasting resulted in beneficial effects that met or exceeded those of caloric restriction including reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress. Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake.

Analysis of Variance↗
PubMed2003

Intermittent fasting and dietary supplementation with 2-deoxy-D-glucose improve functional and metabolic cardiovascular risk factors in rats.

Hypertension and insulin resistance syndrome are risk factors for cardiovascular disease, and it is therefore important to identify interventions that can reduce blood pressure and improve glucose metabolism. We performed experiments aimed at determining whether intermittent fasting (IF) can improve cardiovascular health and also tested the hypothesis that beneficial effects of IF can be mimicked by dietary supplementation with 2-deoxy-D-glucose (2DG) a non-metabolizable glucose analog. Four-month-old male rats were implanted with telemetry probes to allow continuous monitoring of heart rate, blood pressure, physical activity, and body temperature. Rats were then maintained for 6 months on one of three different dietary regimens: ad libitum feeding, IF, or 2DG supplementation. Rats on the IF regimen consumed 30% less food over time and had reduced body weights compared with rats fed ad libitum, whereas rats on the 2DG regimen did not reduce their food intake and maintained their body weight. Heart rate and blood pressure were significantly decreased within 1 month in rats on IF and 2DG diets and were maintained at reduced levels thereafter. Body temperature was significantly decreased in group IF, but not in group 2DG. Levels of serum glucose and insulin were significantly decreased in rats maintained on IF and 2DG-supplemented diets, suggesting that IF and 2DG diets affect insulin sensitivity in a similar manner. Finally, rats in groups IF and 2DG exhibited increased levels of plasma adrenocorticotropin and corticosterone, indicating that these diets induced a stress response. We conclude that reductions in blood pressure, heart rate, and insulin levels, similar to or greater than those obtained with regular physical exercise programs, can be achieved by IF and by dietary supplementation with 2DG by a mechanism involving stress responses.

Animals↗
PubMed2003

Will caloric restriction and folate protect against AD and PD?

Recent epidemiologic studies of different sample populations have suggested that the risk of AD and PD may be increased in individuals with high-calorie diets and in those with increased homocysteine levels. Dietary restriction and supplementation with folic acid can reduce neuronal damage and improve behavioral outcome in mouse models of AD and PD. Animal studies have shown that the beneficial effects of dietary restriction result, in part, from increased production of neurotrophic factors and cytoprotective protein chaperones in neurons. By keeping homocysteine levels low, folic acid can protect cerebral vessels and can prevent the accumulation of DNA damage in neurons caused by oxidative stress and facilitated by homocysteine. Although further studies are required in humans, the emerging data suggest that high-calorie diets and elevated homocysteine levels may render the brain vulnerable to neurodegenerative disorders.

Adult↗