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PubMed2006

Striatal modulation of cAMP-response-element-binding protein (CREB) after excitotoxic lesions: implications with neuronal vulnerability in Huntington's disease.

Recent evidence has shown that the activity of cAMP responsive element-binding protein (CREB) and of CREB-binding protein (CBP) is decreased in Huntington's disease (HD) [Steffan et al. (2000)Proc. Natl Acad. Sci. USA, 97, 6763-6768; Gines et al. (2003)Hum. Mol. Genet., 12, 497-508; Rouaux et al. (2004) Biochem. Pharmacol., 68, 1157-1164; Sugars et al. (2004)J. Biol. Chem., 279, 4988-4999]. Such decrease is thought to reflect the impaired energy metabolism observed in a HD mouse model, where a decline in striatum cAMP levels has been observed [Gines et al. (2003)Hum. Mol. Genet., 12, 497-508]. Increased levels of CREB have also been demonstrated to exert neuroprotective functions [Lonze & Ginty (2002)Neuron, 35, 605-623; Lonze et al. (2002)Neuron, 34, 371-385]. Our study aimed to investigate the distribution of CREB in the neuronal subpopulations of the striatum in normal rats compared to the HD model of quinolinic acid lesion. Twenty-five Wistar rats were administered quinolinic acid 100 mm into the right striatum, and killed after 24 h, 48 h, 1 week, 2 weeks, and six weeks, respectively. The contralateral striata were used as controls. Dual-label immunofluorescence was employed using antibodies against phosphorylated CREB and each of the different neuronal subpopulations markers. Our results show that activated CREB levels decrease progressively in projection neurons and parvalbumin (PARV) and calretinin (CALR) interneurons, whereas such levels remain stable in cholinergic and somatostatin interneurons. Thus, we speculate that the ability of cholinergic interneurons to maintain their levels of CREB after excitotoxic lesions is one of the factors determining their protection in Huntington's disease.

Animals↗
PubMed2000

Differential expression of HSC73 and HSP72 mRNA and proteins between young and adult gerbils after transient cerebral ischemia: relation to neuronal vulnerability.

This study presents a quantitative comparison of the time courses and regional distribution of both constitutive HSC73 and inducible HSP72 mRNA expression and their respective encoded proteins between young (3-week-old) and adult (3-month-old) gerbil hippocampus after transient global ischemia. The constitutive expression of HSC73 mRNA and protein in the hippocampus of the young sham-operated gerbils was significantly higher than in the adults. The HSC73 mRNA expression after ischemia in the CA1 layer of young gerbils was greater than in adult gerbils. HSC73 immunoreactivity was not significantly changed after ischemia-reperfusion in adult hippocampus, whereas it decreased in young gerbils. Ischemia-reperfusion led to induction of HSP72 mRNA expression throughout the hippocampus of both young and adult gerbils. HSP72 mRNA induction was more intense and sustained in the CA1 subfield of young gerbils; this was associated with a marked induction of HSP72 proteins and neuronal survival. The transient expression of HSP72 mRNA in the CA1 layer of adult gerbils was not associated with a subsequent synthesis of HSP72 protein but was linked to neuronal loss. Expression of HSP72 mRNA was shifted to an earlier period of reflow in CA3 and dentate gyrus (DG) subfields of young animals. These findings suggest that the induction of both HSP72 mRNA and proteins in the CA1 pyramidal neurons of young gerbils, as well as the higher constitutive expression of HSC73, may partially contribute to higher neuronal resistance of young animals to transient cerebral ischemia.

Aging↗
PubMed2006

Astrocyte-neuron vulnerability to prenatal stress in the adult rat brain.

Chronic activation of the stress response during pregnancy has been shown to be injurious to the development of the offspring. We have previously demonstrated that restraint prenatal stress inflicted during the last week of pregnancy in rats increased dopamine and glutamate receptors in forebrain areas of the adult offsprings. In this study, the same prenatal insult was employed to assess morphological changes in astrocytes and in the dendritic arborization in frontal cortex, striatum, and hippocampus of the adult rat brain. On postnatal day 90, brains were processed for immunocytochemistry using primary antibodies to glial fibrillary acidic protein (GFAP; the main cytoskeletal astroglial protein), S100B protein (an astroglial-derived neurotrophic factor), MAP-2 (a microtubule-associated protein present almost exclusively in dendrites), and synaptophysin (Syn; one major integral protein of the synaptic vesicles membrane). The results show a significant increase in the cell area of GFAP-immunoreactive (-IR) astrocytes, with high levels of S100B protein and a significant decrease in the relative area of MAP-2-IR neuronal processes in prenatally stressed adult rats. The expression of synaptophysin decreased in all areas studied. These results demonstrate that prenatal stress induces a long-lasting astroglial reaction and a reduced dendritic arborization, with synaptic loss in the brain of adult offspring. In addition to the neurochemical alterations previously reported, these morphological changes might be underlying the behavioral and learning impairment previously observed in prenatally stressed rats.

Animals↗
PubMed2000

Pathological tau phenotypes. The weight of mutations, polymorphisms, and differential neuronal vulnerabilities.

In tauopathies, comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. Six tau isoforms are found in human brain that contain either three (3R) or four microtubule-binding domains (4R). In Alzheimer's disease, all six of the tau isoforms are phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau 55, 64, and 69). In corticobasal degeneration and progressive supranuclear palsy, only phosphorylated 4R-tau isoforms aggregate and appear as a major tau doublet (tau 64 and 69). In Pick's disease, only phosphorylated 3R-tau isoforms aggregate into filaments and are characterized by another major tau doublet (tau 55 and 64). Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in frontotemporal dementia with parkinsonism linked to chromosome 17. In the present study, the question of a relationship between tau isoforms and cell morphology is raised. To answer this question, stably transfected human neuroblastoma SY5Y cell lines with either 3R- or 4R-tau isoforms are established. Cell morphology and tau phosphorylation were modified, suggesting that cells undergo profound changes in their metabolism and viability.

Alzheimer Disease↗
PubMed1986

Selective neuronal vulnerability to hypoxia in vitro.

Hippocampal slices were subjected to a sequence of hypoxic periods of progressively increasing duration. In all slices, synaptic transmission returned during reoxygenation in the fascia dentata, but not in CA1. Thus, the relative vulnerability of CA1 and the fascia dentata to ischemia in situ can be replicated by a purely hypoxic insult in vitro.

Animals↗
PubMedDate not supplied

Kainic acid seizures and the reversibility of calcium loading in vulnerable neurons in the hippocampus.

The threshold pathological changes in the rat hippocampus following systemic administration of kainic acid (12-15 mg/kg) have been studied in relation to i the duration of EEG seizure activity and ii calcium accumulation in post-synaptic neurons, using the oxalate-pyroantimonate method. The reversibility of the pathological changes and calcium loading has been studied from 40 min to 48 h after the termination of seizure activity. Little or no changes were visible 2-3 h after 12 mg kainic acid per kg, but changes were obvious in most hippocampi directly after 2-3.5 h of seizure activity induced by 15 mg kainic acid per kg. These consisted of generalized swelling of perineuronal and perivascular astrocytic processes, neuronal hyperchromasia and microvacuolation, and swelling of CA1 basal dendrites. 'Ischaemic cell change' occurred in a small number of pyramidal neurons. Calcium accumulated in mitochondria of basal dendrites and in the soma of pyramidal neurons in CA1 and CA3. Astrocytic and dendritic swelling and mitochondrial calcium accumulation were rapidly reversed during 40 min of seizure suppression with diazepam. Calcium accumulation in astrocytic processes recovered more slowly (greater than or equal to 4 h). After a recovery period of 24-48 h, ischaemic cell changes were seen only in very occasional pyramidal neurons. The pattern of pathological changes is very similar to that seen after L-allylglycine or bicuculline-induced seizures. If the dendritic and other changes are a direct consequence of agonist actions at excitatory amino acid receptors (pre- or post-synaptic) then similar actions must be occurring in seizures induced by agents acting primarily on GABAergic inhibition.

Animals↗
PubMed2002

Overexpression of copper/zinc superoxide dismutase in transgenic rats protects vulnerable neurons against ischemic damage by blocking the mitochondrial pathway of caspase activation.

Mitochondria are known to be involved in the early stage of apoptosis by releasing cytochrome c, caspase-9, and the second mitochondria-derived activator of caspases (Smac). We have reported that overexpression of copper/zinc superoxide dismutase (SOD1) reduced superoxide production and ameliorated neuronal injury in the hippocampal CA1 subregion after global ischemia. However, the role of oxygen free radicals produced after ischemia/reperfusion in the mitochondrial signaling pathway has not been clarified. Five minutes of global ischemia was induced in male SOD1-transgenic (Tg) and wild-type (Wt) littermate rats. Cytosolic expression of cytochrome c and Smac and activation of caspases were evaluated by immunohistochemistry, Western blot, and caspase activity assay. Apoptotic cell death was characterized by DNA nick end and single-stranded DNA labeling. In the Wt animals, early superoxide production, mitochondrial release of cytochrome c, Smac, and cleaved caspase-9 were observed after ischemia. Active caspase-3 was subsequently increased, and 85% of the hippocampal CA1 neurons showed apoptotic DNA damage 3 d after ischemia. Tg animals showed less superoxide production and cytochrome c and Smac release. Subsequent active caspase-3 expression was not evident, and only 45% of the neurons showed apoptotic DNA damage. A caspase-3 inhibitor (N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone) reduced cell death only in Wt animals. These results suggest that overexpression of SOD1 reduced oxidative stress, thereby attenuating the mitochondrial release of cytochrome c and Smac, resulting in less caspase activation and apoptotic cell death. Oxygen free radicals may play a pivotal role in the mitochondrial signaling pathway of apoptotic cell death in hippocampal CA1 neurons after global ischemia.

Animals↗
PubMed1994

Immunolocalization of calpain I-mediated spectrin degradation to vulnerable neurons in the ischemic gerbil brain.

Transient ischemia-induced perturbations in calcium homeostasis have been proposed to lead to pathological activation of the cysteine protease calpain I and subsequent delayed neuronal death in the CA1 region of hippocampus. We report here on the design and characterization of antibodies selective for calpain-generated fragments of brain spectrin, and their use for immunoblot and immunohistochemical analyses of calpain activation following cerebral ischemia in the gerbil. Although spectrin was susceptible to degradation in vitro by many mammalian proteases, only calpain degraded spectrin to generate fragments immunoreactive with the antibodies. Following 5 min of global ischemia, immunoreactivity for calpain-degraded spectrin was rapidly (within 30 min) and markedly elevated in the perikarya and dendrites of several populations of forebrain neurons. The rapid calpain activation was completely prevented by the NMDA receptor antagonist MK-801. At later times postischemia, but prior to frank neuronal necrosis, calpain-degraded spectrin was restricted to hippocampal area CA1 pyramidal neurons. Silver impregnation histochemistry confirmed that neuronal damage was confined to area CA1. The results indicate that while nonpathological NMDA receptor stimulation can activate calpain, only those neurons showing sustained calpain activation are destined to die.

Amino Acid Sequence↗
PubMed1991

Developmental expression, compartmentalization, and possible role in excitotoxicity of a putative NMDA receptor protein in cultured hippocampal neurons.

The mechanisms regulating the expression and localization of excitatory amino acid (EAA) neurotransmitter receptors in neurons of the developing mammalian brain, and roles for these receptors in the plasticity and degeneration of neural circuits are not well understood. We previously isolated and characterized a 71 kDa glutamate binding protein (GBP) from rat brain, and have recently obtained evidence that this GBP is a component of a functional N-methyl-D-aspartate (NMDA) receptor-ion channel complex. We have now used antibodies to this putative NMDA receptor protein to examine its expression and localization, and consequences of its activation in cultured embryonic (18 day) rat hippocampal neurons. Immunocytochemistry and Western blots using monoclonal antibodies to the GBP demonstrated an increase in GBP-positive neurons and their staining intensity with time in culture. GBP was localized to the somata and dendrites of pyramidal-like neurons and was sparse or absent in the axons. The expression and compartmentalization of GBP occurred in isolated neurons indicating that direct cell interactions were not required for these processes. Cell surface staining for GBP occurred in patches on the soma and dendrites. The developmental expression of GBP immunoreactivity closely paralleled the expression of sensitivity to NMDA neurotoxicity. There was a direct relationship between GBP immunoreactivity and neuronal vulnerability to glutamate-induced degeneration; vulnerable neurons stained heavily whereas resistant neurons showed either low levels of staining or no staining. Finally, a GBP antiserum greatly reduced NMDA neurotoxicity (but not kainate neurotoxicity). Taken together, these findings demonstrate the expression of presumptive NMDA receptors within a subpopulation of embryonic hippocampal neurons, and their segregation to the soma and dentrites of pyramidal neurons. This spatial distribution of glutamate receptors among and within neurons is likely to play important roles in regulating the structure of neural circuitry during development, and may also be an important determinant of selective neuronal vulnerability in pathological conditions.

Animals↗
PubMed1989

Tau protein immunoreactivity in dementia of the Alzheimer type. I. Morphology, evolution, distribution, and pathogenetic implications.

The author has used two monoclonal antibodies against tau, Tau-1 and Tau-2, to study at the light microscopic level the morphology, evolution, and distribution of tau immunoreactivity in 21 cases with dementia of the Alzheimer type (DAT) with clinical histories of dementia ranging from 6 months to 10-15 years. They included four cases with Alzheimer's disease (AD), 14 cases with senile dementia of the Alzheimer type (SDAT), and three demented patients with Down's Syndrome (DS). The morphology and distribution of tau immunoreactivity was similar in all three forms of DAT, but the rapidity of evolution, as judged by the duration of dementia and the amount of immunoreactivity, was most severe in DS with dementia and least severe in SDAT. Excessive tau immunoreactivity, as compared with controls which were negative, was present in both astrocytes and vulnerable neurons. Tau-2-positive astrocytes were present throughout the brain and even in regions with no neuronal vulnerability. In evolving cases, several regions that in full-blown cases showed neuronal involvement contained only labeled astrocytes. The neurofibrillary tangles in neuronal involvement contained only labeled astrocytes. The neurofibrillary tangles in neuronal perikarya, the neurites in senile plaques, and an abundance of abnormal neurites found diffusely in the neuropil were intensely stained. In addition, stained granules (ribosomes) were present in both astrocytes and vulnerable neurons. The senile plaques frequently developed around and, on serial sectioning, were almost constantly associated with blood vessels. The amyloid core in senile plaques and the congophilic vessels were unstained. In cases with the shortest duration of dementia, tau immunoreactivity in neurons was found only in the amygdala, the subiculum, the Sommer's sector, the nucleus raphe dorsalis, locus ceruleus, and nucleus basalis of Meynert. In evolving cases, the depths of sulci were more severely affected than the crests of gyri, and the temporoparietal association cortex was more severely involved than the frontal cortex, but, in advanced cases, the depths of sulci, the crests of gyri, and the entire association cortex were equally affected.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
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↗
PubMed2006

Mitochondriopathy in Parkinson disease and amyotrophic lateral sclerosis.

The causes of the selective neurodegeneration in Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS) are unknown and commonalities among these and other age-related neurodegenerative diseases continue to be sought. Morphologic, biochemical, molecular genetic, and cell/animal model studies suggest that mitochondria might be a convergence point for neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress. In PD, mutations in putative mitochondrial proteins have been identified recently and mitochondrial DNA mutations have been found in nigral neurons. In ALS, changes occur in mitochondrial respiratory chain enzymes and in mitochondrial cell death proteins, indicative of an activation of programmed cell death pathways. Mouse models are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria in neuronal death processes ranging from apoptosis to necrosis. This review presents how malfunctioning mitochondria might contribute to neuronal death in PD and ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2006

100 years and counting: prospects for defeating Alzheimer's disease.

This week marks a century since the first description of Alzheimer's disease (AD). Despite approval of several drugs for AD, the disease continues to rob millions of their memories and their lives. Fortunately, many new therapies directly targeting the mechanisms underlying AD are now in the pipeline. Among the investigative AD therapies in clinical trials are several strategies to block pathogenic amyloid-beta peptides and to rescue vulnerable neurons from degeneration. Complementary but less mature strategies aim to prevent the copathogenic effects of apolipoprotein E and the microtubule-associated protein tau. New insights into selective neuronal vulnerability and the link between aging and AD may provide additional entry points for therapeutic interventions. The predicted increase in AD cases over the next few decades makes the development of better treatments a matter of utmost importance and urgency.

Alzheimer Disease↗
PubMed2001

A depletable pool of adenosine in area CA1 of the rat hippocampus.

Adenosine plays a major modulatory and neuroprotective role in the mammalian CNS. During cerebral metabolic stress, such as hypoxia or ischemia, the increase in extracellular adenosine inhibits excitatory synaptic transmission onto vulnerable neurons via presynaptic adenosine A(1) receptors, thereby reducing the activation of postsynaptic glutamate receptors. Using a combination of extracellular and whole-cell recordings in the CA1 region of hippocampal slices from 12- to 24-d-old rats, we have found that this protective depression of synaptic transmission weakens with repeated exposure to hypoxia, thereby allowing potentially damaging excitation to both persist for longer during oxygen deprivation and recover more rapidly on reoxygenation. This phenomenon is unlikely to involve A(1) receptor desensitization or impaired nucleoside transport. Instead, by using the selective A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine and a novel adenosine sensor, we demonstrate that adenosine production is reduced with repeated episodes of hypoxia. Furthermore, this adenosine depletion can be reversed at least partially either by the application of exogenous adenosine, but not by a stable A(1) agonist, N(6)-cyclopentyladenosine, or by endogenous means by prolonged (2 hr) recovery between hypoxic episodes. Given the vital neuroprotective role of adenosine, these findings suggest that depletion of adenosine may underlie the increased neuronal vulnerability to repetitive or secondary hypoxia/ischemia in cerebrovascular disease and head injury.

Adenosine↗
PubMed1997

Kainate induces the expression of the DNA damage-inducible gene, GADD45, in the rat brain.

The expression of the novel growth arrest and DNA damage-inducible gene GADD45 was examined in kainate-induced epileptic brain damage in the rat using in situ hybridization, northern blot analysis, western blot analysis and immunocytochemistry. Systemic administration of kainate resulted in DNA damage and neuronal degeneration in vulnerable neurons of limbic regions, including the amygdala and hippocampal pyramidal layers, as shown by in situ DNA nick end-labelling and histological staining. GADD45 messenger RNA was transiently increased in non-vulnerable neurons (2-8 h after kainate injection) but was persistently elevated in vulnerable neurons (up to 24 h after injection) after kainate injection. GADD45 protein was elevated in both vulnerable and non-vulnerable neurons at 4 h, but levels decreased in vulnerable neurons thereafter, suggesting that translational blockage of GADD45 protein occurred in these cells. GADD45 protein was overexpressed in non-vulnerable neurons up to 72 h after kainate injection. Because GADD45 may participate in the DNA excision repair process and because it has been shown to be overexpressed in neurons that survive focal cerebral ischaemia, these results support the hypothesis that GADD45 may have a protective role in the injured brain.

Animals↗
PubMed2005

Losing neurons: selective vulnerability and mesial temporal sclerosis.

Mesial temporal sclerosis (MTS) is found in about two-thirds of patients with refractory temporal lobe epilepsy (TLE), and surgical removal of the sclerotic structures eliminates seizures in the majority of cases undergoing surgical resection. Although multiple factors have been implicated in the genesis of MTS, it is still unclear why some individuals are more likely to develop hippocampal sclerosis than others. Epileptologists have proposed that there must be at least two factors involved-an initial precipitating injury (IPI), such as a prolonged febrile seizure, CNS infection, or head trauma, and a second factor that increases vulnerability to neuronal injury. This has been termed the "two-hit hypothesis." Three of the many factors that could possibly heighten susceptibility to neuronal injury and MTS are discussed here. These are microdysgenesis, hippocampal dysgenesis, prior seizures, and genetic predisposition. We conclude that there is currently no compelling evidence to support a role for microdysgenesis in MTS. Hippocampal dysgenesis, on the other hand, may account for febrile seizures and possibly MTS in a small subpopulation of patients with TLE. Additional larger studies are needed to confirm these findings. Experimental evidence indicates that an epileptogenic hippocampus can result from prolonged febrile seizures in infant rats, even though these seizures do not cause MTS in the rat. It is not known if this pathophysiological sequence occurs in humans. Lastly, there appears to be a strong genetic component that predisposes some individuals to MTS, regardless of whether they experience an IPI.

Animals↗