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Results for “selective vulnerability”

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PubMed2003

Loss of calbindin-D28k from aging human cholinergic basal forebrain: relation to neuronal loss.

Cholinergic neurons of the basal forebrain (BFCN) are selectively vulnerable in neurodegenerative disorders of the elderly, particularly in Alzheimer's disease (AD). We investigated age-related changes in the BFCN that may serve as a substrate for this vulnerability. We report a substantial and selective age-related loss of the calcium binding protein calbindin-D(28K) (CB) from the human BFCN. Unbiased stereological estimation indicated that, in individuals under age 65 years, 72% of the choline acetyltransferase (ChAT)-positive BFCN contained CB immunoreactivity. In individuals over age 65 years, only 28% of the BFCN contained CB immunoreactivity, a dramatic loss of 61%. Similar results were obtained using neuronal counts from matching single- or double-stained sections in a larger cohort. The loss of CB immunoreactivity was neurochemically specific. No age-related changes were observed in the number of ChAT- or low-affinity nerve growth factor receptor (p75(NTR))-immunoreactive profiles. The loss of CB was greatest in very old individuals, in whom a small loss of BFCN was observed. Furthermore, the loss of CB displayed the same pattern as the loss of BFCN in AD and was more substantial in the posterior compared with the anterior BFCN sector, suggesting a role for CB in the selective vulnerability of BFCN in AD. The depletion of CB from the BFCN is likely to deprive these neurons of the capacity to buffer high levels of intracellular Ca(2+) and thus to leave them vulnerable to pathological processes, such as those in neurodegenerative disorders, which can cause increased intracellular Ca(2+), thus leading to their degeneration.

Adult↗

PubMed1993

Sequential alteration of [3H]rolipram binding in gerbil brain after transient cerebral ischemia.

The time course of rolipram (Ca2+/calmodulin independent cyclic adenosine monophosphate inhibitor) binding sites changes following gerbil transient forebrain ischemia was determined using receptor autoradiography. Gerbils subjected to 10-min ischemia revealed a significant reduction in rolipram binding in most selectively vulnerable regions early in the recirculation (1-5 h). Marked reduction in the rolipram binding was seen in the selectively vulnerable areas 48 h or 7 days after ischemia. Thereafter, the rolipram binding in the hippocampal CA1 and CA3 sectors, which were most vulnerable to ischemia, was severely reduced up to 1 month after recirculation. In contrast, the reduction of the rolipram binding activity in other regions recovered to sham-operated level or showed a slight recovery. Interestingly, the dentate gyrus, which was resistant to ischemia, also exhibited a significant reduction of the rolipram binding activity up to 1 month after ischemia. Eight months after ischemia, the hippocampal CA1 and CA3 sectors showed severe shrinkage and marked reduction in the rolipram binding. Other regions exhibited no significant reduction in the rolipram binding except for a slight reduction in the thalamus. These results demonstrate that transient cerebral ischemia causes severe reduction in rolipram binding sites in selectively vulnerable areas, and this reduction precedes the neuronal cell loss. These findings may reflect the alteration of an intracellular phosphodiesterase activity after ischemia.

Animals↗

PubMed1990

Neuronal damage and calcium accumulation following transient cerebral ischemia in the rat.

The purpose of this study was to examine the distribution of neuronal damage following transient cerebral ischemia in the rat model of four-vessel occlusion utilizing light microscopy as well as 45Ca-autoradiography. Transient ischemia was induced for 30 min. The animals were allowed to survive for 7 d after ischemia. In the animals subjected to ischemia, the most frequently and seriously damaged areas were the paramedian region of hippocampus, the hippocampal CA1 sector, and the dorsolateral part of striatum, followed by the inferior colliculus, the substantia nigra, the frontal cortex, and the thalamus, which were moderate damaged. Furthermore, the cerebellar Purkinje neurons, the hippocampal CA4 sector, the medial geniculate body, and the hippocampal CA3 sector were slightly affected. 45Ca-autoradiographyic study also revealed calcium accumulation in the identical sites of ischemic neuronal damage, except for the frontal cortex. Regional cerebral blood flow during 10 min of ischemia was severely decreased in selectively vulnerable areas. The blood flow in the medial geniculate body, the substantia nigra, the inferior colliculus, and the cerebellum was less pronounced than that in the selectively vulnerable areas. The present study demonstrates that transient cerebral ischemia can produce significant neuronal damage not only in the selectively vulnerable regions, but also in the brainstem.

Animals↗

PubMedDate not supplied

Selective neuronal vulnerability and the distribution of N-methyl-D-aspartate (NMDA) receptors.

N-Methyl-D-Aspartate (NMDA) receptors are believed to play a critical role in excitotoxic cell death in the CNS. The distribution of NMDA-preferring binding sites is compared here with the patterns of selective neuronal death observed in Alzheimer's disease and following transient ischemia. The distribution of NMDA receptors, by itself, is unable to account for the characteristic patterns of selective neuronal vulnerability observed in conjunction with these types of neuropathology.

Alzheimer Disease↗

PubMed1993

Effects of dimethylthiourea on selective neuronal vulnerability in forebrain ischemia in rats.

BACKGROUND AND PURPOSE: Attempts have been made to characterize conditions under which oxygen free radicals contribute to ischemic brain damage. According to one hypothesis, free radicals are likely mediators of damage only when ischemia is of such long duration that infarction develops or when either preischemic hyperglycemia or hyperthermia is present. The objective of the present study was to explore whether 15 minutes of forebrain ischemia, an insult that leads to selective neuronal vulnerability but not to infarction, is accompanied by production of pathogenetically important free radicals. METHODS: Using a histopathological end point, we studied amelioration of damage by a free radical scavenger, dimethylthiourea, administered in a dose of 750 mg/kg i.p. 60 minutes before ischemia. To study whether this insult leads to detectable protein oxidation we assessed the activity of glutamine synthetase and of carbonyl compounds in the soluble protein fraction. RESULTS: In control animals, the transient ischemia resulted in the expected damage to vulnerable neurons in hippocampus, caudoputamen, and neocortex after 7 days of recovery. Glutamine synthetase activity in caudoputamen and hippocampus and carbonyl content in the soluble protein fraction after 90 minutes of recovery were not affected. However, dimethylthiourea significantly reduced damage to hippocampus and caudoputamen (p < 0.001) and neocortex (p < 0.005). CONCLUSIONS: Lack of evidence of protein oxidation supports the notion that 15 minutes of forebrain ischemia results in a limited insult, confined to the neurons. Provided that unspecific effects can be excluded, the results obtained with dimethylthiourea suggest that free radicals contribute to selective neuronal necrosis.

Animals↗

PubMed2004

Gene expression profiles in microdissected neurons from human hippocampal subregions.

Pyramidal neurons in hippocampal subregions are selectively vulnerable in certain disease states. To investigate, we tested the hypothesis that selective vulnerability in human hippocampus is related to regional differences in neuronal cell death and cell receptor gene expression in CA1 vs. CA3 subregions. We used laser capture microdissection to remove approximately 600 CA1 and 600 CA3 pyramidal neurons each from five fresh-frozen normal post-mortem brains, extracted total RNA and double-amplified mRNA. This was reverse transcribed and labeled for hybridization onto human cDNA array chips containing probes to 10,174 genes and unknown ESTs. RNA from additional microdissections was pooled for replicate hybridizations and quantitative RT-PCR validation. Gene expression differences were few (< 1%). We found 43 enriched genes in CA1 neuronal samples that included peripheral benzodiazipine receptor-associated protein, nicotinic cholinergic receptor, two chemokine receptors (CCR1 and CCR5) and several transcriptional factors. We found 17 enriched genes in the CA3 neuronal samples that included fibroblast growth factor receptor and prostaglandin-endoperoxide synthase 1. We found no differential gene expression for 23 calcium channel proteins; nine transporter proteins; 55 cell death and apoptotic regulator proteins; and an additional 497 cell receptors, including 24 glutamate receptors. Quantitative RT-PCR of four differentially expressed genes confirmed the microarray data. The results confirm the ability to examine gene expression profiles in microdissected neurons from human autopsy brain. They show only minor gene expression differences between two distinct neuronal populations in the hippocampus and suggest that selective hippocampal vulnerability is due to factors other than intrinsic differential expression in glutamate receptors and cell death genes.

Gene Expression↗

PubMed2006

The changes in endogenous antioxidant enzyme activity after postconditioning.

1. The aim of this work was to study potential mechanisms participating in postischemic protection of selectively vulnerable CA1 neurons in the hippocampus. Experiments were focused on measuring changes in endogenous antioxidant enzyme activity. 2. Forebrain cerebral ischemia was induced in a rat by four-vessel occlusion. Ten minutes of ischemia induces so-called delayed neuronal death in selectively vulnerable CA1 region 3 days later. After 7 days of reperfusion, 71.6% of neurons succumb to neurodegeneration. When 5 min of ischemia was used as postconditioning, 2 days after 10 min of cerebral ischemia, delayed neuronal death in CA1 was almost completely (89.9%) prevented. 3. Searching for mechanisms of protection, we measured the activity of endogenous antioxidant enzymes. Activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were measured in the hippocampus, striatum and cortex by spectrophotometric methods after 10 min of ischemia used as the preconditioning. Two days after the preconditioning or the sham operation, second ischemia was induced for 5 min. We observed significant increase of total SOD activity in all studied regions of the brain 5 h after postconditioning (5 min of ischemia). SOD activity decreased to control values after 24 h. 4. In some experiments, we used intraperitoneal injections of norepinephrine (3.1 microM/kg) or 3-nitropropionic acid (20 mg/kg) as postconditioning, instead of ischemia. All three treatments resulted in significant increase of SOD activity, but norepinephrine was the most effective. The same effect as was seen for total SOD activity could be observed for CuZn-SOD as well as Mn-SOD activity. Similarly, considerable increase in the activity of catalase was detected 5 h after postconditioning (5 min of ischemia). It is interesting that the greatest changes were established in selectively vulnerable hippocampus and striatum. As in the case of SOD, the highest levels of CAT activity were induced by norepinephrine, while lower but significant increase in CAT activity was induced by 3-nitropropionic acid.5. Our results suggest that endogenous antioxidants SOD and CAT could play considerable neuroprotective role after postconditioning.

Animals↗

PubMedDate not supplied

Selective functional vulnerability of cortical neurons following transient MCA-occlusion in the cat.

Simultaneous recordings of several cortical neurons were obtained before, during and after transient 15 min occlusion of the middle cerebral artery in cats. With the use of a multiple electrode array consisting of 4-7 platinum/iridium microelectrodes, the cortical pericellular blood flow was concurrently measured by means of the hydrogen clearance technique. Hydrogen clearance measurements revealed a homogeneous blood flow distribution throughout all phases of the experiment in the area covered by the different microelectrodes. Considering only the results of experiments with low residual blood flow during ischemia (less than 0.1 ml/g/min), single unit activity ceased immediately after occlusion and remained so during the ischemic period. The recovery time of action potentials after reperfusion ranged from 10 min to 3 hours depending on the examined neuron. Lower values for discharge rates of the individual cells were generally observed after reoccurrence, although some units exhibited temporarily an even higher spike frequency. Furthermore, the spike form usually changed in that the hyperpolarizing afterpotentials were enlarged after recirculation. However, some cells with a nearly unchanged spike form were found as well. The results indicate that the recovery of cell function largely depends on the individual neuron which supports the idea of a selective functional vulnerability of cortical neurons in response to ischemia.

Action Potentials↗

PubMed2004

Effects of intracerebroventricular application of brain-derived neurotrophic factor on cerebral recovery after cardiac arrest in rats.

SUBJECT: After transient global cerebral ischemia, selective vulnerable brain areas show delayed neurodegeneration with characteristics of apoptosis. Recent data demonstrate potent neuroprotective effects of the application of endogenous growth hormones such as brain-derived neurotrophic factor (BDNF) after focal cerebral ischemia. To assess possible effects of the intracerebroventricular application of BDNF on cerebral recovery after global cerebral ischemia due to cardiac arrest in rats, various selective vulnerable brain areas were investigated. INTERVENTIONS: Global cerebral ischemia was initiated by ventricular fibrillation in rats under general anesthesia. After 6 mins, the animals were resuscitated by external cardiac massage combined with defibrillation and divided into two groups (BDNF vs. placebo). BDNF or placebo (1 microg/hr) was applied continuously during the complete reperfusion time using an implanted osmotic minipump. After 6 hrs, 24 hrs, 3 days, and 7 days (n = 6-7 per group), coronal brain sections were analyzed by terminal deoxynucleotidyltransferase-mediated d-uracil triphosphate-biotin nick end-labeling (TUNEL) and Nissl staining and a caspase activity assay in the hippocampal cornu ammonis 1 sector, the nucleus reticularis thalami, and the striatum. At 24 hrs, 3 days, and 7 days, animals were tested according to a neurologic deficit score. MEASUREMENTS AND MAIN RESULTS: In all groups, typical delayed neurodegeneration was observed in selective vulnerable brain areas. Neuroscore, TUNEL, and Nissl staining revealed no relevant differences between the groups (BDNF vs. placebo) with regard to neurologic recovery and the number of viable (after 7 days in cornu ammonis 1 sector: BDNF, 110 +/- 32; placebo, 142 +/- 53) and TUNEL-positive neurons (after 7 days in cornu ammonis 1 sector: BDNF, 360 +/- 81; placebo, 253 +/- 62) during the different time points. CONCLUSIONS: Despite the well-known neuroprotective properties of BDNF in ischemic-induced neuronal degeneration, the present study did not reveal any beneficial effects regarding neurologic recovery and neurohistopathologic outcome after global cerebral ischemia in rats. Future investigations should focus on intracellular signaling cascades activated by BDNF after global cerebral ischemia.

Animals↗

PubMed1998

Selective neuronal vulnerability and specific glial reactions in hippocampal and neocortical organotypic cultures submitted to ischemia.

Neurons from cerebral neocortex and hippocampus exhibit a striking difference in vulnerability to transient global ischemia. In order to study the contribution of neuronal connections and neuron-glia interactions to this variation in neuronal vulnerability, we used hippocampal and neocortical cultures submitted to various periods of histotoxic ischemia. Organotypic cultures were exposed at 37 degrees C for 0, 7, 30 and 60 min to a glucose-free NaCN-containing medium. Histological analysis using thionin staining and MAP2 immunostaining showed differences in the temporal profile of neuronal damage in hippocampal and neocortical structures, i.e., in decreasing order, CA1 (7 min) > CA3 and neocortical layers II, III, V, VI (30 min) > DG and neocortical layer IV (60 min). In parallel to the neurodegeneration study, the time course and the regional pattern of microglial and astroglial changes were also examined using GS-B4 isolectin and GFAP as immunohistochemical markers, respectively. The GS-B4 isolectin staining revealed an early (at 7 min for the hippocampus) and a specific microglial activation located in areas undergoing neuronal damage. For both organotypic cultures, astrogliosis occurred later (after 30 min of stress) with no specific regional distribution. Both hippocampal and neocortical cultures submitted to histotoxic ischemia allowed the replication of many of the cellular events observed in response to global ischemia in vivo. These findings support the hypothesis that neuron-neuron connections as well as interactions between neurons and glial cells are essential to reproduce in vitro the selective neuronal vulnerability described in vivo.

Adaptation, Physiological↗

PubMed1995

Post-ischemic changes of [3H]glycine binding in the gerbil brain after cerebral ischemia.

Sequential changes of [3H]glycine binding in the gerbil were investigated in selectively vulnerable areas 1 h to 7 days after 10 min of cerebral ischemia. A significant reduction in [3H]glycine binding was found in the hippocampus and thalamus from as early as 1 h after ischemia. In contrast, the striatum and frontal cortex showed a significant decline in [3H]glycine binding from 5 h after recirculation. Thereafter, a severe reduction in [3H]glycine binding was observed in all regions 7 days after ischemia. MAP2 (microtubule-associated protein 2) immunoreactivity was unaffected in the hippocampus, frontal cortex and thalamus up to 48 h after ischemia. Thereafter, a severe loss of MAP2-immunoreactive neurons was found in these regions, especially in the hippocampal CA1 sector. However, the striatum showed a severe loss of MAP2 immunoreactivity from 24 h after ischemia. These results demonstrate that transient cerebral ischemia causes severe reduction in [3H]glycine binding throughout the brain, and this reduction precedes the neuronal damage in selectively vulnerable areas. These findings suggest that a neurotransmitter, glycine, may play a key role in the pathogenesis of post-ischemic neurodegeneration in selectively vulnerable areas.

Animals↗

PubMed1995

Selective acid vulnerability of dopaminergic neurons and its recovery by brain-derived neurotrophic factor.

Among the pathogenetic phenomena of Parkinson's disease, the character of the selective degeneration of nigrostriatal system with severe gliosis is not fully understood. Here, we have shown that dopaminergic neurons may be exclusively sensitive to elevated acidity elicited after the addition of glial mitogenic factors such as epidermal growth factor and basic fibroblast growth factor or after the direct treatment with hydrochloric acid. The acid sensitivity was specific to dopaminergic neurons. The neurons other than dopaminergic neurons in culture from the ventral mesencephalon were not sensitive to acidity and the neurons from several brain areas were the same as above, except for the hippocampal neurons which had slight acid vulnerability. Choline acetyltransferase assay studies demonstrated that the cholinergic neuronal population in the septum and corpus striatum had no acid sensitivity. The vulnerability of dopaminergic neurons either elicited by glial mitogenic factor or derived from the direct acid exposure was inhibited by the addition of brain-derived neurotrophic factor (BDNF), but not by neurotrophin-3 or nerve growth factor. These findings suggest that dopaminergic neurons have selective acid vulnerability on which BDNF has a pronounced protective effect.

Acids↗

PubMed1999

Sodium influx plays a major role in the membrane depolarization induced by oxygen and glucose deprivation in rat striatal spiny neurons.

BACKGROUND AND PURPOSE: Striatal spiny neurons are selectively vulnerable to ischemia, but the ionic mechanisms underlying this selective vulnerability are unclear. Although a possible involvement of sodium and calcium ions has been postulated in the ischemia-induced damage of rat striatal neurons, the ischemia-induced ionic changes have never been analyzed in this neuronal subtype. METHODS: We studied the effects of in vitro ischemia (oxygen and glucose deprivation) at the cellular level using intracellular recordings and microfluorometric measurements in a slice preparation. We also used various channel blockers and pharmacological compounds to characterize the ischemia-induced ionic conductances. RESULTS: Spiny neurons responded to ischemia with a membrane depolarization/inward current that reversed at approximately -40 mV. This event was coupled with an increased membrane conductance. The simultaneous analysis of membrane potential changes and of variations in [Na+]i and [Ca2+]i levels showed that the ischemia-induced membrane depolarization was associated with an increase of [Na+]i and [Ca2+]i. The ischemia-induced membrane depolarization was not affected by tetrodotoxin or by glutamate receptor antagonists. Neither intracellular BAPTA, a Ca2+ chelator, nor incubation of the slices in low-Ca2+-containing solutions affected the ischemia-induced depolarization, whereas it was reduced by lowering the external Na+ concentration. High doses of blockers of ATP-dependent K+ channels increased the membrane depolarization observed in spiny neurons during ischemia. CONCLUSIONS: Our findings show that, although the ischemia-induced membrane depolarization is coupled with a rise of [Na+]i and [Ca2+]i, only the Na+ influx plays a prominent role in this early electrophysiological event, whereas the increase of [Ca2+]i might be relevant for the delayed neuronal death. We also suggest that the activation of ATP-dependent K+ channels might counteract the ischemia-induced membrane depolarization.

Adenosine Triphosphate↗

PubMed2003

Regional differences of somatic CAG repeat instability do not account for selective neuronal vulnerability in a knock-in mouse model of SCA1.

Expression of unstable translated CAG repeats is the mutational mechanism in nine different neurodegenerative disorders. Although the products of genes harboring these repeats are widely expressed, a subset of neurons is vulnerable in each disease accounting for the different phenotypes. Somatic instability of the expanded CAG repeat has been implicated as a factor mediating the selective striatal neurodegeneration in Huntington disease. It remains unknown, however, whether such a mechanism contributes to the selective neurodegeneration in other polyglutamine diseases or not. To address this question, we investigated the pattern of CAG repeat instability in a knock-in mouse model of spinocerebellar ataxia type 1 (SCA1). Small pool PCR analysis on DNA from various neuronal and non-neuronal tissues revealed that somatic repeat instability was most remarkable in the striatum. In the two vulnerable tissues, cerebellum and spinal cord, there were substantial differences in the profiles of mosaicism. These results suggest that in SCA1 there is no clear causal relationship between the degree of somatic instability and selective neuronal vulnerability. The finding that somatic instability is most pronounced in the striatum of various knock-in models of polyglutamine diseases highlights the role of trans-acting tissue- or cell-specific factors in mediating the instability.

Animals↗

PubMed2005

Rat brain serotonin neurones that express neuronal nitric oxide synthase have increased sensitivity to the substituted amphetamine serotonin toxins 3,4-methylenedioxymethamphetamine and p-chloroamphetamine.

Substituted amphetamines such as p-chloroamphetamine and the abused drug methylenedioxymethamphetamine cause selective destruction of serotonin axons in rats, by unknown mechanisms. Since some serotonin neurones also express neuronal nitric oxide synthase, which has been implicated in neurotoxicity, the present study was undertaken to determine whether nitric oxide synthase expressing serotonin neurones are selectively vulnerable to methylenedioxymethamphetamine or p-chloroamphetamine. Using double-labeling immunocytochemistry and double in situ hybridization for nitric oxide synthase and the serotonin transporter, it was confirmed that about two thirds of serotonergic cell bodies in the dorsal raphé nucleus expressed nitric oxide synthase, however few if any serotonin transporter immunoreactive axons in striatum expressed nitric oxide synthase at detectable levels. Methylenedioxymethamphetamine (30 mg/kg) or p-chloroamphetamine (2 x 10 mg/kg) was administered to Sprague-Dawley rats, and 7 days after drug administration there were modest decreases in the levels of serotonin transporter protein in frontal cortex, and striatum using Western blotting, even though axonal loss could be clearly seen by immunostaining. p-Chloroamphetamine or methylenedioxymethamphetamine administration did not alter the level of nitric oxide synthase in striatum or frontal cortex, determined by Western blotting. Analysis of serotonin neuronal cell bodies 7 days after p-chloroamphetamine treatment, revealed a net down-regulation of serotonin transporter mRNA levels, and a profound change in expression of nitric oxide synthase, with 33% of serotonin transporter mRNA positive cells containing nitric oxide synthase mRNA, compared with 65% in control animals. Altogether these results support the hypothesis that serotonin neurones which express nitric oxide synthase are most vulnerable to substituted amphetamine toxicity, supporting the concept that the selective vulnerability of serotonin neurones has a molecular basis.

3,4-Methylenedioxyamphetamine↗

PubMed1992

Energy metabolism and selective neuronal vulnerability following global cerebral ischemia.

A short period of global ischemia results in the death of selected subpopulations of neurons. Some advances have been made in understanding events which might contribute to the selectivity of this damage but the cellular changes which culminate in neuronal death remain poorly defined. This overview examines the metabolic state of tissue in the post-ischemic period and the relationship of changes to the development of damage in areas containing ischemia-susceptible neurons. During early recirculation there is substantial recovery of ATP, phosphocreatine and related metabolites in all brain regions. However, this recovery does not signal restitution of normal energy metabolism as reductions of the oxidative metabolism of glucose are seen in many areas and may persist for several days. Furthermore, decreases in pyruvate-supported respiration develop in mitochondria from at least one ischemia-susceptible region at times coincident with the earliest histological evidence of ischemia-induced degeneration. These mitochondrial changes could simply be an early marker of irreversible damage but the available evidence is equally consistent with these contributing to the degenerative process and offering a potential site for therapeutic intervention.

Animals↗

PubMed2004

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.

Animals↗

PubMed1999

Differential expression of group I metabotropic glutamate receptors in rat spinal cord somatic and autonomic motoneurons: possible implications for the pathogenesis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of somatic, but not autonomic, motoneurons. The reason for this selective vulnerability is unknown. The pathogenesis of ALS is thought to involve glutamatergic excitotoxic mechanisms. While overactivation of ionotropic glutamate receptors may trigger excitotoxicity, we have previously shown that stimulation of group I metabotropic glutamate receptors (mGluRs) can exert neuroprotective effects on cultured motoneurons. Using in situ hybridization, we found a differential expression of group I mGluRs (mGluR1 and 5) in rat spinal cord. Autonomic motoneurons from the sacral parasympathetic Onuf's nucleus and thoracic sympathetic neurons, which are spared in ALS, express high levels of mGluR5, while somatic motoneurons do not. In addition, mGluR1 mRNA is found only in smaller somatic motoneurons, which seem to be less vulnerable in ALS. Thus, differential mGluR expression might provide a possible clue to the selective vulnerability of different motoneuronal subpopulations in ALS.

Amyotrophic Lateral Sclerosis↗