Biomedical subjects

M P Mattson

Publications and source records attributed to M P Mattson.

At least 181 records · Page 10Linked to original sources

PubMed1998

Lysophosphatidic acid induces necrosis and apoptosis in hippocampal neurons.

A diverse body of evidence indicates a role for the lipid biomediator lysophosphatidic acid (LPA) in the CNS. This study identifies and characterizes the induction of neuronal death by LPA. Treatment of cultured hippocampal neurons from embryonic rat brains with 50 microM LPA resulted in neuronal necrosis, as determined morphologically and by the release of lactate dehydrogenase. A concentration of LPA as low as 10 microM led to the release of lactate dehydrogenase. In contrast, treatment of neurons with 0.1 or 1.0 microM LPA resulted in apoptosis, as determined by chromatin condensation. In addition, neuronal death induced by 1 microM LPA was characterized as apoptotic on the basis of terminal dUTP nick end-labeling (TUNEL) staining, externalization of phosphatidylserine, and protection against chromatin condensation, TUNEL staining, and phosphatidylserine externalization by treatment with N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad-spectrum inhibitor of caspases, i.e., members of the interleukin-1beta converting enzyme family. Studies with antagonists of ionotropic glutamate receptors did not indicate a significant role for these receptors in apoptosis induced by 1 microM LPA. LPA (1 microM) also induced a decrease in mitochondrial membrane potential. Moreover, pretreatment of neurons with cyclosporin A protected against the LPA-induced decrease in mitochondrial membrane potential and neuronal apoptosis. Thus, LPA, at pathophysiological levels, can induce neuronal apoptosis and could thereby participate in neurodegenerative disorders.

Animals↗

PubMed1998

Astrocytic gap junctional communication decreases neuronal vulnerability to oxidative stress-induced disruption of Ca2+ homeostasis and cell death.

We investigated the effect of uncoupling astrocytic gap junctions on neuronal vulnerability to oxidative injury in embryonic rat hippocampal cell cultures. Mixed cultures (neurons growing on an astrocyte monolayer) treated with 18-alpha-glycyrrhetinic acid (GA), an uncoupler of gap junctions, showed markedly enhanced generation of intracellular peroxides (2,7-dichlorofluorescein fluorescence), impairment of mitochondrial function [(dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction], and cell death (lactate dehydrogenase release) following exposure to oxidative insults (FeSO4 and 4-hydroxynonenal). GA alone had little or no effect on basal levels of peroxides, mitochondrial function, or neuronal survival. Intercellular dye transfer analyses revealed extensive astrocyte-astrocyte coupling but no astrocyte-neuron or neuron-neuron coupling in the mixed cultures. Studies of pure astrocyte cultures and microscope analyses of neurons in mixed cultures showed that the increased oxidative stress and cell death in GA-treated cultures occurred only in neurons and not in astrocytes. Antioxidants (propyl gallate and glutathione) blocked the death of neurons exposed to FeSO4/GA. Elevations of neuronal intracellular calcium levels ([Ca2+]i) induced by FeSO4 were enhanced in neurons in mixed cultures exposed to GA. Removal of extracellular Ca2+ and the L-type Ca2+ channel blocker nimodipine prevented impairment of mitochondrial function and cell death induced by FeSO4 and GA, whereas glutamate receptor antagonists were ineffective. Finally, GA exacerbated kainate- and FeSO4-induced injury to pyramidal neurons in organotypic hippocampal slice cultures. The data suggest that interastrocytic gap junctional communication decreases neuronal vulnerability to oxidative injury by a mechanism involving stabilization of cellular calcium homeostasis and dissipation of oxidative stress.

Administration, Topical↗

PubMed1998

The transcription factor NF-kappaB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons.

Tumor necrosis factor-alpha (TNF alpha) is a cytokine rapidly produced in the brain in response to vigorous neuronal activity and tissue injury. TNF alpha may protect neurons against excitotoxic and oxidative insults by a mechanism involving activation of the transcription factor NF-kappaB. Whole-cell perforated patch clamp recordings in cultured rat hippocampal neurons showed that long-term treatment (24-48 h) with TNF alpha increases Ca2+ current density; pharmacological analysis indicated a major increase in current through L-type voltage-dependent calcium channels. Long-term treatment with TNF alpha caused a decrease in currents induced by glutamate, NMDA, AMPA, and kainate. Shorter exposures to TNF alpha (acute; 2 h) did not alter Ca2+ current or glutamate receptor agonist-induced currents. Ceramide, an intracellular messenger that activates the transcription factor NF-kappaB, mimicked the actions of TNFs on Ca2+ current density and currents induced by glutamate receptor agonists. Cotreatment with kappaB decoy DNA abolished the effects of TNF alpha on Ca2+ current and excitatory amino acid-induced currents, demonstrating a requirement for NF-kappaB activation in the actions of TNF alpha. Neurons pretreated with TNF alpha exhibited increased intracellular Ca2+ concentrations following membrane depolarization but reduced intracellular Ca2+ concentration responses to excitatory amino acids, compared with neurons in untreated control cultures or cultures cotreated with kappaB decoy DNA. These findings suggest important roles for the transcription factor NF-kappaB in modulation of voltage-dependent calcium channels and glutamate receptors and the many physiological and pathophysiological processes in which these ion channels are involved. Such signaling mechanisms may be particularly important in injury settings such as ischemia or trauma, where TNF alpha expression is increased and NF-kappaB is activated.

Animals↗

PubMed1998

Traumatic brain injury alters synaptic homeostasis: implications for impaired mitochondrial and transport function.

This study utilized a unilateral controlled cortical impact model of traumatic brain injury to assess disruptions of synaptic homeostasis following trauma. Adult rats were subjected to a moderate (2 mm) cortical deformation and synaptosomes were prepared from the entire ipsilateral (injured) hemisphere or dissected into different regions (hippocampus, injured cortical area including penumbra, residual hemisphere) at various times postinjury (10 and 30 min, and 1, 6, and 24 h). Synaptosomes from the corresponding regions of the contralateral hemisphere were used as controls to assess alterations in synaptic ATP levels, lipid peroxidation, and glutamate and glucose transport. The results demonstrate significant time-dependent alterations in synaptic homeostasis, which included an immediate reduction in ATP levels, coupled with a significant increase in lipid peroxidation within 30 min postinjury. Lipid peroxidation demonstrated a biphasic response with elevations observed 24 h postinjury, a time at which decreases in glutamate and glucose transport occurred. These results suggest that disruption of synaptic homeostasis is an extremely early event following trauma that should be considered when designing pharmacological interventions.

Adenosine Triphosphate↗

PubMed1998

Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor.

Ischemic and excitotoxic insults to the brain induce rapid production of tumor necrosis factor-alpha (TNF), but the role of TNF in neuronal responses to brain injury are unclear. Two different TNF receptors (p55 and p75) are expressed in neurons and glia. To understand the role of TNF in brain injury, we generated mice that lack p55, p75, or both receptors. We report that neuronal damage after focal cerebral ischemia-reperfusion is significantly increased in mice lacking p55 receptors (85+/-7 mm3 infarct volume; mean +/- SD) compared with wild-type mice (70+/-8 mm3) and mice lacking p75 receptors (72+/-6 mm3). Moreover, mice lacking p55 receptors exhibited increased degeneration of CA3 hippocampal neurons after administration of the excitotoxin kainic acid compared with wild-type mice and mice lacking p75 receptors. When taken together with recent data showing that TNF can prevent apoptosis of cultured neurons exposed to oxidative and metabolic insults, our findings suggest that TNF plays a neuroprotective role after acute brain insults.

Animals↗

PubMed1998

4-Hydroxynonenal, a product of lipid peroxidation, damages cholinergic neurons and impairs visuospatial memory in rats.

The mechanisms that underlie cholinergic neuronal degeneration in Alzheimer disease (AD) are unclear, but recent data suggest that oxidative stress plays a role. We report that 4-hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, damages and kills basal forebrain cholinergic neurons when administered intraparenchymally. Examination of Nissl-stained brain sections following unilateral HNE infusion revealed widespread neuronal loss in basal forebrain ipsilateral to the injection, but not on the contralateral side. Levels of choline acetyltransferase activity and immunoreactivity in the ipsilateral basal forebrain and hippocampus were significantly reduced by 60-80% seven days following HNE administration. Performance in Morris water maze tasks of visuospatial memory was severely impaired in a dose-dependent manner seven days following bilateral administration of HNE. Bilateral infusion of FeCl2 (an inducer of membrane lipid peroxidation) into the basal forebrain caused neuron loss and decreased choline acetyltransferease immunoreactivity and deficits in visuospatial memory. Additionally, FeCl2 infusion increased HNE immunoreactivity, implicating HNE in iron-induced oxidative damage. Because recent studies have demonstrated HNE adducts in degenerating neurons in AD brain, the present findings suggest a role for HNE in damage to cholinergic neurons in AD.

Aldehydes↗

PubMed1998

Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system.

Free radicals are known to occur as natural by-products under physiological conditions and have been implicated in the neuronal loss observed in a variety of neuropathological conditions including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and ischemia. Oxyradical-induced cytotoxicity arises from both chronic and acute increases in reactive oxygen species which give rise to subsequent lipid peroxidation (LP). By reacting with polyunsaturated fatty acids in the the various cellular membranes, oxyradicals such as hydroxyl (OH.) and peroxynitrite (ONOO) give rise to a variety of lipid peroxidation products (LPP), including 4-hydroxynonenal (HNE) and malondialdehyde (MD). Once formed, these peroxidation metabolites have been demonstrated to have relatively long half-lives within cells (minutes to hours), allowing for multiple interactions with cellular components. Emerging data suggest that LP and LPP may underlie the neuronal alterations and neurotoxicity observed in numerous neurodegenerative conditions. Data supporting this involvement include the detection of LP and formation of LPP in a variety of neuropathological conditions including AD, ALS, PD, and ischemia. Secondly, direct application of LPP, either in vivo or in vitro, has been shown to be cytotoxic and mimic neuronal alterations observed in neuropathological conditions. Furthermore, prevention of LP and subsequent LPP formation have been demonstrated to be neuroprotective in a variety of neurodegenerative paradigms. Additionally, LP and LPP have been implicated in the modulation of a wide array of activities within the central nervous system including long term potentiation, neurite outgrowth, and proliferation. Understanding the mechanism(s) and involvement of LP in these processes will greatly enhance the understanding of oxyradical and ion homeostasis in neurophysiological and neuropathological conditions. The focus of this review is to describe the process by which lipid peroxidation occurs and establish a framework for its involvement in the central nervous system.

Animals↗

PubMed1998

Signaling events regulating the neurodevelopmental triad. Glutamate and secreted forms of beta-amyloid precursor protein as examples.

During development of the nervous system a common set of signal transduction pathways appear to regulate growth cone behaviors, synaptogenesis and natural cell death, three fundamental processes that comprise the "neurodevelopmental triad". Among the intercellular signals that coordinate the developmental triad in the mammalian brain are glutamate (the major excitatory neurotransmitter) and beta-amyloid precursor protein (beta APP). Localization of ionotropic glutamate receptors to dendritic compartments allows for selective regulation of dendrite growth cones and spine formation by glutamate released from axonal growth cones and presynaptic terminals. Expression of particular subtypes of glutamate receptors peaks during a developmental time window within which synaptogenesis and natural neuronal death occur. Calcium is the preeminent second messenger mediating both acute (rapid remodelling of the microtubule and actin cytoskeletal systems) and delayed (transcriptional regulation of growth-related proteins; e.g., neurotrophins) actions of glutamate. The expression of beta APP in brain is developmentally regulated and it is expressed ubiquitously in differentiated neurons. beta APP is axonally transported and secreted forms of beta APP (sAPPs) are released from neurons in an activity-driven manner. Secreted APPs modulate neuronal excitability, counteract effects of glutamate on growth cone behaviors, and increase synaptic complexity. Acute actions of sAPPs appear to be transduced by cyclic GMP which promotes activation of K+ channels and reduces [Ca2+]i. Delayed actions of sAPPs may involve regulation of gene expression by the transcription factor NF kappa B. Finally, the striking effects of glutamate, neurotrophic factors, and sAPPs on synaptogenesis and neuronal survival in cell culture systems and in vivo suggest that each of these signals plays major roles in the process of natural cell death. The same signalling mechanisms that mediate adapative regulation of neuroarchitecture during brain development appear to play prominent roles in maladaptive neurodegenerative processes in an array of disorders ranging from stroke to epilepsy to Alzheimer's disease.

Amyloid beta-Protein Precursor↗

PubMed1997

Estrogens stabilize mitochondrial function and protect neural cells against the pro-apoptotic action of mutant presenilin-1.

Mutations in presenilin-1 (PS-1) account for approximately half the cases of autosomal dominant early-onset Alzheimer's disease (AD). Recent data indicate that PS-1 mutations may render neurons vulnerable to apoptosis induced by various insults. We now report that 17beta-estradiol, which appears to reduce the risk of sporadic AD, protects cultured PC12 cells expressing mutant PS-1 against apoptosis induced by trophic factor withdrawal (TFW) and exposure to amyloid beta-peptide 25-35 (Abeta). Estriol also provided significant protection against apoptosis induced by TFW and Abeta, whereas corticosterone was ineffective. 17beta-Estradiol prevented decreases in mitochondrial transmembrane potential and energy charge/redox state following exposure of cells to TFW and Abeta in control cell lines and lines expressing mutant PS-1, suggesting an action in the apoptotic pathway upstream of mitochondrial alterations. Abeta caused an increase in mitochondrial reactive oxygen species which was enhanced by mutant PS-1, and suppressed by 17beta-estradiol. The ability of 17beta-estradiol to preserve mitochondrial function, suppress oxidative stress, and counteract the pro-apoptotic actions of mutant PS-1 suggests a generalized neuroprotective action of estrogens in both sporadic and inherited forms of AD.

Amino Acid Substitution↗

PubMed1997

Cell and molecular neurobiology of presenilins: a role for the endoplasmic reticulum in the pathogenesis of Alzheimer's disease?

Mutations in genes encoding presenilin-1 (PS-1) and presenilin-2 (PS-2) cause many cases of autosomal dominant inherited forms of early-onset Alzheimer's disease (AD). PSs are expressed in neurons throughout the nervous system, with differences in abundance among cell populations. PS-1 and PS-2 each have six to eight transmembrane domains and are localized mainly in the endoplasmic reticulum (ER). PSs may interact with cytoskeletal proteins and beta-amyloid precursor protein (APP) in ways consistent with roles in membrane trafficking and APP processing. Expression of mutant PSs in cultured cells and transgenic mice results in increased production of an amyloidogenic-cytotoxic form of amyloid beta-peptide (Abeta). Neural cells expressing mutant PSs exhibit increased sensitivity to apoptosis induced by trophic factor withdrawal and Abeta. The proapoptotic action of mutant PSs involves perturbed calcium release from ER stores and increased levels of oxidative stress. PS mutations may also suppress neurotransmitter synthesis in cholinergic neurons, suggesting a role in regulation of neuronal phenotype. Homology of PSs with the C. elegans gene sel-12 and phenotypic similarities of PS-1 and Notch knockout mice suggest a developmental role for PSs in somitogenesis. Collectively, the emerging data suggest intriguing roles of PSs in neuronal plasticity and cell death and highlight the importance of the ER as a regulatory site involved in the pathogenesis of neuronal degeneration in AD.

Alzheimer Disease↗

PubMed1997

17Beta-estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid beta-peptide and iron.

Synapse loss, deposits of amyloid beta-peptide (Abeta), impaired energy metabolism, and cognitive deficits are defining features of Alzheimer's disease (AD). Estrogen replacement therapy reduces the risk of developing AD in postmenopausal women. Because synapses are likely sites for initiation of neurodegenerative cascades in AD, we tested the hypothesis that estrogens act directly on synapses to suppress oxidative impairment of membrane transport systems. Exposure of rat cortical synaptosomes to Abeta25-35 (Abeta) and FeSO4 induced membrane lipid peroxidation and impaired the function of the plasma membrane Na+/K+-ATPase, glutamate transporter, and glucose transporter. Pretreatment of synaptosomes with 17beta-estradiol or estriol largely prevented impairment of Na+/K+-ATPase activity, glutamate transport, and glucose transport; other steroids were relatively ineffective. 17Beta-estradiol suppressed membrane lipid peroxidation induced by Abeta and FeSO4, but did not prevent impairment of membrane transport systems by 4-hydroxynonenal (a toxic lipid peroxidation product), suggesting that an antioxidant property of 17beta-estradiol was responsible for its protective effects. By suppressing membrane lipid peroxidation in synaptic membranes, estrogens may prevent impairment of transport systems that maintain ion homeostasis and energy metabolism, and thereby forestall excitotoxic synaptic degeneration and neuronal loss in disorders such as AD and ischemic stroke.

Amyloid beta-Peptides↗

PubMed1997

The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excitotoxicity in hippocampal neurons.

Calcium influx through NMDA receptors and voltage-dependent calcium channels (VDCC) mediates an array of physiological processes in neurons and may also contribute to neuronal degeneration and death in neurodegenerative conditions such as stroke and severe epileptic seizures. Gelsolin is a Ca2+-activated actin-severing protein that is expressed in neurons, wherein it may mediate motility responses to Ca2+ influx. Primary hippocampal neurons cultured from mice lacking gelsolin exhibited decreased actin filament depolymerization and enhanced Ca2+ influx after exposure to glutamate. Whole-cell patch-clamp analyses showed that currents through NMDA receptors and VDCC were enhanced in hippocampal neurons lacking gelsolin, as a result of decreased current rundown; kainate-induced currents were similar in neurons containing and lacking gelsolin. Vulnerability of cultured hippocampal neurons to glutamate toxicity was greater in cells lacking gelsolin. Seizure-induced damage to hippocampal pyramidal neurons was exacerbated in adult gelsolin-deficient mice. These findings identify novel roles for gelsolin in controlling actin-mediated feedback regulation of Ca2+ influx and in neuronal injury responses. The data further suggest roles for gelsolin and the actin cytoskeleton in both physiological and pathophysiological events that involve activation of NMDA receptors and VDCC.

Actins↗

PubMed1997

Abeta25-35 induces rapid lysis of red blood cells: contrast with Abeta1-42 and examination of underlying mechanisms.

Amyloid beta-peptide (A beta) is produced by many different cell types and circulates in blood and cerebrospinal fluid in a soluble form. In Alzheimer's disease (AD), A beta forms insoluble fibrillar aggregates that accumulate in association with cells of the brain parenchyma and vasculature. Both full-length A beta (A beta1-40/42) and the A beta25-35 fragment can damage and kill neurons by a mechanism that may involve oxidative stress and disruption of calcium homeostasis. Circulating blood cells are exposed to soluble A beta1-40/42 and may also be exposed to A beta aggregates associated with the luminal surfaces of cerebral microvessels. We therefore examined the effects of A beta25-35 and A beta1-42 on human red blood cells (RBCs) and report that A beta25-35, in contrast to A beta1-42, induces rapid (10-60 min) lysis of RBCs. The mechanism of RBC lysis by A beta25-35 involved ion channel formation and calcium influx, but did not involve oxidative stress because antioxidants did not prevent cell lysis. In contrast, A beta1-42 induced a delayed (4-24 h) damage to RBCs which was attenuated by antioxidants. The damaging effects of both A beta25-35 and A beta1-42 towards RBCs were completely prevented by Congo red indicating a requirement for peptide fibril formation. A beta1-42 induced membrane lipid peroxidation in RBC, and basal levels of lipid peroxidation in RBCs from AD patients were significantly greater than in age-matched controls, suggesting a possible role for A beta1-42 in previously reported alterations in RBCs from AD patients.

Adult↗

PubMed1997

Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration.

The transcription factor NF-kappaB is expressed in neurons wherein it is activated in response to a variety of stress- and injury-related stimuli including exposure to cytokines such as tumor necrosis factor-alpha (TNFalpha), and excitotoxic and oxidative insults. NF-kappaB may play a role in the anti-death actions of TNFalpha in cultured hippocampal neurons exposed to metabolic and oxidative insults. We now report that pretreatment of hippocampal cell cultures with agents that activate NF-kappaB (TNFalpha and C2-ceramide) confers resistance of neurons to apoptosis induced by the oxidative insults FeSO4 and amyloid beta-peptide (Abeta25-35). The neuroprotective actions of TNFalpha and ceramide were abolished in cultures cotreated with kappaB decoy DNA demonstrating a requirement for NF-kappaB activation for prevention of cell death. Levels of manganese superoxide dismutase (Mn-SOD) in neurons were increased following exposure of cultures to TNFalpha and ceramide in control cultures, but not in cultures cotreated with kappaB decoy DNA. FeSO4 and Abeta25-35 induced accumulation of mitochondrial peroxynitrite, and membrane lipid peroxidation, in neurons. Peroxynitrite accumulation and lipid peroxidation were largely prevented in neurons pretreated with TNFalpha and ceramide prior to exposure to FeSO4 and Abeta25-35, an effect blocked by kappaB decoy DNA. Immunoreactivity of neurons with an anti-nitrotyrosine antibody was increased following exposure to FeSO4 and Abeta25-35; TNFalpha and C2-ceramide suppressed protein tyrosine nitration, and kappaB decoy DNA blocked the effects of TNFalpha and C2-ceramide. Finally, the peroxynitrite scavenger uric acid protected neurons against apoptosis induced by FeSO4 and Abeta, and suppressed peroxynitrite accumulation. We conclude that, by inducing production of Mn-SOD and suppressing peroxynitrite formation and membrane lipid peroxidation, NF-kappaB plays an anti-apoptotic role in neurodegenerative conditions that involve oxidative stress. The data further suggest important roles for peroxynitrite and NF-kappaB in the pathogenesis of neuronal degeneration in Alzheimer's disease.

Animals↗

PubMed1997

Nerve growth factor-independent reduction in choline acetyltransferase activity in PC12 cells expressing mutant presenilin-1.

Mutations in the presenilin genes (PS-1 and PS-2) are linked to early onset familial Alzheimer's disease (AD), but the mechanisms by which these mutations cause the cognitive impairment characteristic of AD are unknown. Basal forebrain cholinergic neurons are involved in learning and memory processes, and reductions in choline acetyl-transferase (ChAT) activity are a characteristic feature of AD brain. We therefore hypothesized that presenilin mutations suppress expression of the cholinergic phenotype. In rat PC12 cells stably transfected with the human PS-1 gene containing the Leu --> Val mutation at codon 286 (L286V), we observed a drastic reduction (>90%) in basal ChAT activity compared with cells transfected with vector alone. By immunocytochemistry, a similar decrease in ChAT protein levels was found in the mutant transfectants. In cells differentiated with nerve growth factor, ChAT activity was again markedly lower in L286V-expressing cells than in control cells. We also observed reductions in ChAT activity in PC12 cells expressing the wild-type human PS-1 gene but to a lesser extent than in L286V-expressing cells. The viability of cells transfected with either the wild-type or the mutant PS-1 gene was not compromised. Our results suggest that PS-1 mutations may contribute to the cognitive impairment in AD by causing a nontoxic suppression of the cholinergic phenotype.

Alzheimer Disease↗

PubMed1997

Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury.

Glutamate-induced excitotoxicity involving the formation of reactive oxygen species (ROS) has been implicated in neuronal dysfunction and cell loss following ischemic and traumatic injury to the central nervous system (CNS). ROS are formed in mitochondria when energy metabolism is compromised, and are inactivated by the ROS scavengers superoxide dismutase (SOD), catalase, and glutathione (GSH). ROS can impair the function of several cellular components including proteins, nucleic acids, and lipids. In the present study, we measured indicators of mitochondrial metabolic activity, ROS formation, lipid peroxidation, and antioxidant enzyme activities in synaptosomes obtained from rat spinal cord at early times following traumatic injury. Mitochondrial metabolic activity was found to significantly decrease as early as 1 h following injury, and continued to be compromised over the remaining postinjury time points. ROS formation was found to be significantly increased at 4 and 24 h following injury, while lipid peroxidation levels were found to be significantly increased in the injured spinal cord at 1 and 24 h, but not 4 h following injury. SOD enzyme activity was unchanged at all postinjury time points, while catalase activity and GSH levels were significantly increased at 24 h following injury. These findings indicate that impaired mitochondrial function, ROS, and lipid peroxidation occur soon after traumatic spinal cord injury, while the compensatory activation of molecules important for neutralizing ROS occurs at later time points. Therapeutic strategies aimed at facilitating the actions of antioxidant enzymes or inhibiting ROS formation and lipid peroxidation in the CNS may prove beneficial in treating traumatic spinal cord injury, provided such treatments are initiated at early stages following injury.

Animals↗

PubMed1997

Secreted form of beta-amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices.

The secreted form of beta-amyloid precursor protein (sAPP alpha) is released from neurons in an activity-dependent manner, and has been reported to modulate neuronal excitability in dissociated hippocampal neurons. We now report that sAPP alpha shifts the frequency dependence for induction of long-term depression of synaptic transmission (LTD) in hippocampal slices from adult rats. Whereas low frequency stimulation (1 Hz) of Schaffer collateral axons induced LTD of the post-synaptic response of CA1 neurons in control slices, it did not induce LTD in slices pretreated with sAPP alpha. On the other hand, whereas a 10 Hz stimulation normally induced neither LTD or LTP, it did induce LTD in slices pretreated with sAPP alpha. sAPP alpha potentiated LTP induced by high frequency stimulation. sAPP alpha induced cGMP production in hippocampal slices, and pretreatment of slices with 8-bromo-cyclic GMP mimicked the effect of sAPP alpha on LTD suggesting a role for cyclic GMP in modulation of LTD. The data suggest an important role for sAPP alpha in modulation of synaptic plasticity in the hippocampus.

Amyloid beta-Protein Precursor↗

PubMed1997

4-Hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau.

In Alzheimer's disease (AD) the microtubule-associated protein tau is excessively phosphorylated in degenerating neurons, but the mechanisms underlying the increased phosphorylation are unknown. Recent findings suggest that oxidative stress, and membrane lipid peroxidation in particular, contributes to the neurodegenerative process in AD. We now report that following exposure of cultured rat hippocampal neurons to 4-hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, tau is resistant to dephosphorylation. Immunocytochemical and Western blot analyses using phosphorylation-sensitive tau antibodies showed that HNE treatment causes a moderate increase in basal levels of tau phosphorylation, and prevents tau dephosphorylation by alkaline phosphatase in neurons pretreated with the phosphatase inhibitor okadaic acid. Studies with anti-HNE antibodies showed that HNE binds directly to tau, and that HNE immunoreactivity localizes to cell bodies and axons, cell compartments that contain tau. These data suggest a role for HNE in altered tau phosphorylation and neurofibrillary degeneration in AD.

Aldehydes↗