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At least 73 records · Page 4Linked to original sources
PubMed1996

Copper/zinc superoxide dismutase expression in the human central nervous system. Correlation with selective neuronal vulnerability.

Oxidative stress has been implicated in the pathogenesis of several neurological disorders. We examined the regional distribution of copper/zinc superoxide dismutase (SOD-1), one of the key antioxidant enzymes, in the human central nervous system using in situ hybridization. Our results show that the enzyme is present at high levels of constitutive expression in alpha-motor neurons, oculomotor neurons, nucleus basalis, substantia nigra, neocortex, and the hippocampal sector resistant to hypoxia (H2). Relatively lower levels were found in Sommer's sector (H1) and Purkinje cells. We conclude that a lower constitutive level of SOD-1 expression may play a role in the selective vulnerability of certain neuronal populations to hypoxia but does not correlate with the patterns of neurodegeneration observed in amyotrophic lateral sclerosis. Parkinson's disease, and Alzheimer's disease.

Adult↗
PubMed2001

Phospholipase A2 mediates ischemic injury in the hippocampus: a regional difference of neuronal vulnerability.

Although it is well known that the hippocampal CA1 subfield is highly vulnerable to ischemic injury, cellular mechanisms leading to this neuronal degeneration are not fully understood. Using organotypic cultures of rat hippocampal slices, we determined whether phospholipase A2 (PLA2) is activated in response to ischemic conditions (OGD; oxygen and glucose deprivation). The PLA2 activity in the pyramidal cell layer increased immediately following a 35-min exposure to OGD, which was likely to be mediated by selective activation of cytosolic Ca2+-dependent PLA2 subtype (cPLA2). This enhancement lasted for at least 24 h. Interestingly, no apparent increase was detected in the dentate gyrus. Twenty-four hours after the OGD exposure, neuronal death was detected mainly in the CA1 region of hippocampal slices. To examine whether the PLA2 activation is causally or protectively involved in the ischemic injury, we investigated the effect of pharmacological blockade of PLA2 on the OGD-induced neuronal death. The PLA2 inhibitor bromophenacyl bromide efficiently prevented the cell death in a concentration-dependent manner. Similar results were obtained for the selective cPLA2 inhibitor AACOCF3. However, the Ca2+-independent PLA2 inhibitor bromoenol lactone and the secretory PLA2 inhibitor LY311727 were virtually ineffective. These results suggest that cPLA2 plays a causative role in the neuronal death following OGD exposure. Thus, the present study may provide novel therapeutic targets for the development of neuroprotective agents.

Animals↗
PubMed2026

Mapping cell-type- and age-dependent neuronal vulnerability through genome-wide in vivo CRISPRi screens in the mouse brain.

Current brain atlases are largely descriptive, cataloging correlative molecular snapshots such as gene expression signatures yet offering limited functional insight. Here, we develop a scalable, cell-type-resolved in vivo CRISPR interference (CRISPRi) platform enabling systematic gene function profiling in the mouse brain. Through genome-wide screens across four neuronal populations at three time points spanning youth to aging, we identify neuronal essential genes missed in vitro and define a consensus set of 269 neuronal core essential genes. The data reveal cell-type-specific genetic vulnerabilities, including divergent dependencies validated for exosome component 9 (Exosc9) and osteopetrosis-associated transmembrane protein 1 (Ostm1) between excitatory and inhibitory neurons. We uncover aging-specific dependencies enriched in mitochondrial and translational pathways, aligning with transcriptional changes in the aging human brain. Finally, we establish the CRISPRinvivo data portal as a community resource for in vivo screening. Altogether, this work provides a broadly applicable platform for in vivo functional genomics and a framework for building comprehensive gene-function brain atlases.

brain aging↗
PubMed2005

Neuronal vulnerability in mouse models of Huntington's disease: membrane channel protein changes.

Huntington's disease (HD) is caused by a polyglutamine expansion that results in atrophy of the striatum and frontal cortex during disease progression. HD-susceptible striatal neurons are affected chronologically with initial degeneration of the striatopallidal neurons then the striatonigral projections, whereas large aspiny striatal interneurons (LAN) survive. Two classes of critical membrane proteins were evaluated in transgenic mouse models to determine their association with HD susceptibility, which leads to dysfunction and death in selected striatal neuron populations. We examined potassium (K+) channel protein subunits that form membrane ionophores conducting inwardly and outwardly rectifying K+ currents. K+ channel protein staining was diminished substantially in the HD striatal projection neurons but was not expressed in the HD-resistant LAN. Because loss of K+ channel subunits depolarizes neurons, other voltage-gated ionophores will be affected. N-methyl-D-aspartate (NMDA) receptors and their phosphorylation by cyclic AMP were studied as a mechanism contributing to excitotoxic vulnerability in striatal projection neurons that would lose voltage regulation after diminished K+ channels. NR1 subunits showed significant elevation in the HD transgenic projection systems but were expressed at very low levels in LAN. NR1 subunit phosphorylation by cyclic AMP also was enhanced in striatal projection neurons but not in LAN. Cyclic AMP-driven phosphorylation of NMDA receptors increases the channel open time and elevates neuronal glutamate responsiveness, which may lead to excitotoxicity. Together our data suggest that changes in these proteins and their modification may predispose striatal projection neurons to dysfunction and then degeneratation in HD and provide a mechanism for LAN resistance in the disease.

Animals↗
PubMed1999

Extracellular reduced glutathione increases neuronal vulnerability to combined chemical hypoxia and glucose deprivation.

In addition to its intracellular antioxidant role, reduced glutathione (GSH) is released by CNS cells and may mediate or modulate excitatory neurotransmission. Although extracellular GSH levels rise in the ischemic cortex, its effect on the viability of energy-compromised neurons has not been defined. In this study, we tested the hypothesis that exogenous GSH would increase the vulnerability of cultured cortical neurons to azide-induced chemical hypoxia combined with glucose deprivation. Thirty minutes azide exposure in a glucose-free buffer was tolerated by most neurons, with release of less than 10% of neuronal LDH over the subsequent 21-25 h. Concomitant treatment with 10-100 microM GSH increased cell death in a concentration-dependent fashion, to 71.6+/-5.1% of neurons at 100 microM; GSH alone was nontoxic. Injury was blocked by the selective N-methyl-d-aspartate (NMDA) antagonist MK-801 but not by the AMPA/kainate antagonist NBQX. The sulfhydryl reducing agent mercaptoethanol (10-100 microM) mimicked the action of GSH; however, the zinc chelator ethylenediaminetetraacetic acid (EDTA) was ineffective. Two GSH analogues that lack a sulfhydryl group, S-hexylglutathione (SHG) and oxidized glutathione (GSSG), were inactive per se but attenuated the effect of both GSH and mercaptoethanol. These results suggest that micromolar concentrations of GSH enhance neuronal loss due to energy depletion by altering the extracellular redox state, resulting in increased NMDA receptor activation.

Animals↗
PubMed2003

Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation.

Loss of mitochondrial membrane integrity and the resulting release of apoptogenic factors may play a critical role in mediating hippocampal neurodegeneration after transient global ischemia. In the present study, the authors have cloned and characterized the rat cDNA encoding apoptosis-inducing factor (AIF), an intramitochondrial protein that promotes cell death in a caspase-independent manner upon release into nonmitochondrial compartments. In contrast to the expression patterns of a number of apoptosis-regulatory gene products during brain development, the expression of AIF protein increases gradually with brain maturation and peaks in adulthood. In a rat model of transient global ischemia, AIF was found to translocate from mitochondria to the nucleus in the hippocampal CA1 neurons after ischemia and to manifest a DNA-degrading activity that mimicked the purified AIF protein and was inhibitable by AIF immunodepletion. The temporal profile of AIF translocation after ischemia (24 to 72 hours) coincided with the induction of large-scale DNA fragmentation at the size of 50 kbp, a well-characterized hallmark of AIF-like activity but preceded the formation of internucleosomal DNA fragmentation (72 hours), a DNA degradation associated with the terminal stage of cell death. Further, the nuclear translocation of AIF after ischemia was not blocked by inhibiting caspase-3/-7 activities, but, as shown in neuronal cultures that were challenged with transient oxygen-glucose deprivation, it can be prevented by intracellular delivery of the mitochondria-associated antiapoptotic protein Bcl-xL. The results presented here strongly suggest that mitochondrial release of AIF may be an important factor, in addition to the previously reported cytochrome c and Smac, which could contribute to the selective vulnerability of CA1 neurons to transient global ischemic injury.

Amino Acid Sequence↗
PubMed1996

Nitric oxide synthase and neuronal vulnerability in Parkinson's disease.

Parkinson's disease is characterized by a loss of dopaminergic neurons in the mesencephalon. Although the mechanism of this neuronal loss is still unknown, oxidative stress is very likely involved in the cascade of events leading to nerve cell death. Since nitric oxide could be involved in the production of free radicals, we analysed, using immunohistochemistry and histochemistry, the production systems of nitric oxide in the mesencephalon of four patients with idiopathic Parkinson's disease and three matched control subjects. Using specific antibodies directed against the inducible isoform of nitric oxide synthase (the enzyme involved in the synthesis of nitric oxide), we found evidence to suggest that this isoform was present solely in glial cells displaying the morphological characteristics of activated macrophages. Immunohistochemical analysis performed with antibodies against the neuronal isoform of nitric oxide synthase, however, revealed perikarya and processes of neurons but no glial cell staining. The number of nitric oxide synthase-containing cells was investigated by histoenzymology, using the NADPH-diaphorase activity of nitric oxide synthase. Histochemistry revealed (i) a significant increase in NADPH-diaphorase-positive glial cell density in the dopaminergic cell groups characterized by neuronal loss in Parkinson's disease and (ii) a neuronal loss in Parkinson's disease that was two-fold greater for pigmented NADPH-diaphorase-negative neurons than for pigmented NADPH-diaphorase-positive neurons. These data suggest a potentially deleterious role of glial cells producing excessive levels of nitric oxide in Parkinson's disease, which may be neurotoxic for a subpopulation of dopaminergic neurons, especially those not expressing NADPH-diaphorase activity. However, it cannot be excluded that the presence of glial cells expressing nitric oxide synthase in the substantia nigra of patients with Parkinson's disease represents a consequence of dopaminergic neuronal loss.

Aged↗
PubMed1994

c-fos protein expression and ischemic changes in neurons vulnerable to ischemia/hypoxia, correlated with basic fibroblast growth factor immunoreactivity.

Injuries to the brain induce rapid expression of c-fos and c-jun proto-oncogenes in neurons. The protein products (Fos and Jun) of these cellular immediate early genes are thought to regulate target genes that participate in fundamental biological responses. In recent studies of rat brain infarct we demonstrated that gliosis and angiogenesis, two of the fundamental biological responses, are related to neuronal expression of basic fibroblast growth factor (bFGF). In the present study, we explore the linkage between c-fos and bFGF genes by comparing the temporal and spatial domains of Fos and bFGF immunoreactivities (IR) in brain infarct and in transient global ischemia. We demonstrate colocalization of Fos-IR and ischemic changes in neurons at infarct periphery and in regions of "selective vulnerability" beginning 3 hours post-infarction and lasting up to 1-2 weeks. These are: cortical neurons in layers II-III and V, interneurons in hippocampal formation, cerebellar Purkinje cells, and many subcortical nuclei and brainstem nuclei. bFGF-IR appears 12-24 hours later than Fos-IR in the same region but in non-ischemic neurons and the expression persists beyond 2 weeks. Persistent and not transient c-fos expression appears to be associated with ischemic neuronal death, although some of these neurons may survive beyond 2 weeks postinfarction.

Animals↗
PubMed2000

The estrogen replacement therapy of the Women's Health Initiative promotes the cellular mechanisms of memory and neuronal survival in neurons vulnerable to Alzheimer's disease.

OBJECTIVES: The current study investigated the neurotrophic and neuroprotective action of the complex formulation of conjugated equine estrogens (CEEs), the most frequently prescribed estrogen replacement therapy in the United States and the estrogen replacement therapy of the Women's Health Initiative. METHODS: Videomicroscopic, morphologic and biochemical analyses were conducted in primary cultures of hippocampal neurons to determine the neurotrophic and neuroprotective properties of CEEs. RESULTS: Results of these analyses demonstrated that CEEs significantly increased hippocampal neuronal outgrowth, a cellular marker of memory formation. Dose response analyses indicated that the lowest effective concentration of CEEs exerted the maximal neurotrophic effect. Results of neuroprotection studies demonstrated that CEES induced highly significant neuroprotection against beta amyloid(25-35), hydrogen peroxide and glutamate-induced toxicity. CONCLUSIONS: CEEs induced cellular markers of memory function in neurons critical to memory and vulnerable to negative effects of aging and Alzheimer's disease. In addition, CEEs significantly and potently protected neurons against toxic insults associated with Alzheimer's disease. Because CEEs are the estrogen replacement therapy of the Women's Health Initiative, results of the current study could provide cellular mechanisms for effects of CEEs on cognitive function and risk of Alzheimer's disease derived from this prospective clinical trial.

Alzheimer Disease↗
PubMed2002

Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer's disease pathology.

In individuals with Alzheimer's disease (AD), there is a two-fold elevation in the serum concentrations of the gonadotropins, luteinizing hormone (LH), and follicle stimulating hormone compared to age-matched controls. Whether this plays a role in disease pathogenesis is unclear. Nonetheless, gonadotropins are known to cross the blood brain barrier and the highest density of gonadotropin receptors in the brain are found within the hippocampus. We report for the first time the localization of LH in the cytoplasm of pyramidal neurons. In addition, we find a significant increase in LH in the cytoplasm of pyramidal neurons and neurofibrillary tangles of AD brain compared to age-matched control brain. Whereas the functional consequences of increased neuronal LH are unknown, it is notable that LH is primarily localized to those neurons that are known to be vulnerable to Alzheimer's disease-related neurodegeneration. Elevated serum and cortical neuron levels of LH, coupled with the decline in sex steroid production, could play important roles in the pathogenesis of AD.

Aged↗
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↗
PubMed1995

Reexpression of developmentally regulated MAP2c mRNA after ischemia: colocalization with hsp72 mRNA in vulnerable neurons.

Levels of mRNAs encoding the microtubule-associated proteins MAP2b and MAP2c as well as the 70-kDa stress protein [72-kDa heat shock protein (hsp72)] were evaluated in postischemic rat brain by in situ hybridization with oligonucleotide probes corresponding to the known rat sequences. Rats were subjected to 10-min cardiac arrest, produced by compression of major thoracic vessels, followed by resuscitation. The normally expressed MAP2b mRNA showed transient twofold elevations in all hippocampal neuron populations at 6-h recirculation, followed by a return to control levels by 24 h. MAP2b hybridization was progressively lost thereafter from the vulnerable CA1 and outer cortical layers, preceding both the fall in immunoreactive MAP2b and the eventual cell loss in these regions. The depletion of MAP2b mRNA coincided with an increase in the alternatively spliced MAP2c in vulnerable regions during 12-48 h of recirculation, precisely overlapping the late component of hsp72 expression that persisted in these cell populations. Previous studies have suggested that the initial induction of hsp72 provides an index of potential postischemic injury in neuron populations that may or may not be injured, while lasting hsp72 mRNA expression is associated with cell damage. In contrast, the present results demonstrate that MAP2c expression under these conditions occurs uniquely in neuron populations subject to injury. Available evidence suggests that MAP2c expression represents a plastic response in subpopulations of neurons that will survive in these regions, although it remains to be explicitly determined whether it may also be transiently expressed in dying cells. In any case, these observations demonstrate that reexpression of developmentally regulated MAP2c mRNA is a relatively late postischemic response in vulnerable cell populations, indicating that pathways regulating MAP2 splicing may be closely associated with mechanisms of neuron injury and/or recovery.

Animals↗
PubMed2002

Tumor necrosis factor alpha increases neuronal vulnerability to excitotoxic necrosis by inducing expression of the AMPA-glutamate receptor subunit GluR1 via an acid sphingomyelinase- and NF-kappaB-dependent mechanism.

Acid sphingomyelinase (ASMase) and NF-kappaB participate in tumor necrosis factor alpha (TNFalpha) signal transduction. Mice in which the genes encoding ASMase or the p50 subunit of NF-kappaB are disrupted have been reported to be less vulnerable than wild-type mice to focal brain ischemia. We now demonstrate selective diminution in expression of GluR1, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type glutamate receptor (AMPA-GluR) protein subunit, in these two groups of knockout mice. To confirm that neuronal GluR1 expression is regulated by ASMase and NF-kappaB, and to learn whether this regulation has pathophysiological significance, we treated cultured human NT2-N neurons with TNFalpha. This induced GluR1 expression and increased susceptibility of the neurons to kainate necrosis. Both induction of GluR1 and heightened vulnerability to kainate were blocked by inhibiting ASMase or by antisense knockdown of NF-kappaB p50. We conclude that TNFalpha can sensitize neurons to excitotoxic necrosis by inducing expression of GluR1 via an ASMase- and NF-kappaB-dependent mechanism. TNFalpha levels are frequently elevated during ischemia and other CNS diseases in which excitotoxicity contributes to neuronal loss. Our results suggest that inhibiting TNFalpha signal transduction will diminish neuronal necrosis in these diseases.

Animals↗
PubMed1996

[Study of androgen receptor expression and neuronal vulnerability in X-linked spinal and bulbar muscular atrophy].

X-linked spinal and bulbar muscular atrophy (SBMA), a rare adult onset form of motor neuron disease, is clinically characterized by slowly progressive muscle weakness and atrophy, and endocrinopathy such as gynecomastia, testicular atrophy and oligospermia. Androgens are known to play an important role in motor neuron growth, development and regeneration. The genetic mutation of androgen receptor (AR) gene in SBMA has been disclosed and thought to lead to degeneration of lower motor neurons. However, the mechanism of neuronal death and the basis for the regional specificity of neuropathology observed in SBMA are not clear. At first, we proved the existence of androgen receptor (AR) in the motor neurons of the rat spinal cord by the immunohistochemical stain and Western blotting. The possibility that AR protein in spinal cord is expressed in tissue-specific form is proposed, being different from other androgen-dependent tissue. Northern blotting data showed that AR is expressed in not only rat spinal cord but also cerebrum and cerebellum, which are spared in SBMA. Then, specimens from 2 SBMA patients were examined and compared with those from normal controls (n = 4). AR was widely expressed in central nervous system. Anterior horn cells, which are severely affected in SBMA, were stained intensely. Even the remaining atrophic motor neurons in SBMA had AR. To our interest, the neurons of cranial nerves III, IV, VI, dentate nucleus, posterior horn and Onufrowicz nucleus etc., which are spared in SBMA, contained AR moderately. These data did not show any difference between SBMA and controls. Our immunohistochemical study showed that not only the neurons affected in SBMA but the unaffected in this disease process express AR. The question why motor neurons are selectively involved in SBMA if AR is present in almost neurons should further be clarified.

Aged↗
PubMed1995

Differential neuronal vulnerability to amino-oxyacetate and quinolinate in the rat parahippocampal region.

Injection of the "indirect" excitotoxin amino-oxyacetate into the entorhinal area causes acute behavioral seizures and preferential neuronal loss in layer III of the medial entorhinal cortex in rats. We examined here whether the effects of amino-oxyacetate could be duplicated by local injections of the endogenous N-methyl-D-aspartate receptor agonist and direct excitotoxin, quinolinate. Amino-oxyacetate (685 nmol) or quinolinate (30, 45 or 60 nmol) were injected into the entorhinal cortex of rats anesthetized with choral hydrate (360 mg/kg). Separate groups of animals were co-treated with the N-methyl-D-aspartate receptor antagonist dizocilpine maleate (2 mg/kg) or given a higher dose of chloral hydrate (500 mg/kg). Rats that received amino-oxyacetate and a low anesthetic dose consistently displayed acute behavioral seizures and showed preferential loss of neurons in layer III of the medial entorhinal cortex. Animals that were given quinolinate did not display behavioral seizures, and showed preferential degeneration of neurons in layer V of the entorhinal cortex. Moreover, quinolinate-injected rats frequently exhibited neuronal loss in the superficial layers of the dorsal perirhinal cortex. The behavioral and neuropathological sequelae of amino-oxyacetate, but not quinolinate-induced neurotoxicity, were abolished by prolonged chloral hydrate anesthesia. In spite of these apparent qualitative differences between the two toxins, neurodegeneration induced by either amino-oxyacetate or quinolinate was completely prevented by dizocilpine maleate. These data suggest that a heterogeneous distribution of pharmacologically distinct N-methyl-D-aspartate receptor subtypes in the parahippocampal region may underlie the distinct neurodegenerative properties of the two toxins. Since the lesion caused by amino-oxyacetate bears remarkable similarities to neuropathological changes which have been described in this structure in temporal lobe epilepsy, further elucidation of the mechanisms of cellular toxicity of amino-oxyacetate may hold clues for the pathogenesis of this disease.

Aminooxyacetic Acid↗