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Results for “selective vulnerability”

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PubMed2005

Endoplasmic reticulum stress compromises the ubiquitin-proteasome system.

The presence of endoplasmic reticulum (ER) stress and impaired ubiquitin-proteasome system (UPS) activity has been independently implicated in the pathophysiology of conformational diseases. Here, we reveal a link between ER stress and the functionality of the UPS. Treatment of cells with different ER stressors delayed the degradation of an ER reporter substrate and caused a subtle but consistent accumulation of three independent nuclear/cytosolic UPS reporter substrates. A similar signature increase was observed upon induction of ER stress in transgenic mice expressing a reporter substrate. Cells undergoing ER stress failed to clear efficiently UBB+1, an aberrant ubiquitin found in conformational diseases, which in turn caused general impairment of the UPS. We conclude that ER stress has a general inhibitory effect on the UPS. The compromised UPS during ER stress may explain the long-term gradual accumulation of misfolded proteins as well as the selective vulnerability of particular cell populations in conformational diseases.

Animals↗

PubMed2001

Hippocampal injury and alterations in neuronal chemokine co-receptor expression in patients with AIDS.

Hippocampal neurons express high levels of HIV chemokine co-receptors, activation of which causes injury or death in vitro. To determine if their in vivo expression correlates with injury, we evaluated neuronal CXCR4 and CCR5 immunoreactivity and reactive gliosis in autopsy hippocampus of 10 control cases, 11 AIDS cases without HIV encephalitis (HIVnE) or opportunistic infections/lymphomas (OI/L), and 11 AIDS cases with HIV encephalitis (HIVE). All groups had higher CXCR4 and CCR5 expression in CA3 and CA4 neurons than CA1 neurons (p < 0.05). HIVE cases had increased neuronal CXCR4 and decreased neuronal CCR5 expression as well as increased numbers of hippocampal GFAP-positive astrocytes and LN3-positive microglia. Changes were most severe in CA3 and CA4 and lowest in CA1 regions. These findings also were noted in the 4 HIVE cases with neither hippocampal HIVE nor brain OI/L and in the HIVnE groups. This study quantitates the regional distribution of hippocampal neuronal CXCR4 and CCR5 and shows their respective increase and decrease in AIDS. It suggests a relationship between neuronal loss and gliosis with intensity of neuronal chemokine expression and raises the possibility of a selective vulnerability of hippocampal neurons to AIDS-related injury.

AIDS Dementia Complex↗

PubMed2001

Detection of HIV-1 gene sequences in hippocampal neurons isolated from postmortem AIDS brains by laser capture microdissection.

We employed laser capture microdissection to remove individual pyramidal neurons from the CA1, CA3, and CA4 regions of formalin-fixed, paraffin-embedded hippocampus from 8 AIDS brains and 2 HIV-1-seronegative normal brains. We amplified HIV-1 gag and nef gene sequences using separate, double round PCR reactions for each of the primer sets. In all 3 hippocampal regions, amplification efficiency was best with sequence length between 284 and 324 bp; HIV-1 nef gene sequences were more common than HIV-1 gag sequences; and rank order for percent positive amplification was CA3 > CA4 > CA1 samples. These results are the first to detect HIV-1 gene sequences in microdissected human tissue. They indicate that brain neurons in vivo contain HIV-1 DNA sequences consistent with latent infection by this virus, and suggest that neurons display a selective vulnerability for HIV infection. Neuronal HIV infection could contribute to neuronal injury and death or act as a potential viral reservoir if reactivated.

AIDS Dementia Complex↗

PubMed2003

Transglutaminase activity, protein, and mRNA expression are increased in progressive supranuclear palsy.

Transglutaminases catalyze the covalent cross-linking of substrate proteins to form insoluble protein complexes that are resistant to degradation. Our previous studies demonstrated that transglutaminase-induced cross-linking of tau proteins occurs in Alzheimer disease and progressive supranuclear palsy (PSP). The current study was designed to measure transglutaminase enzyme activity and the mRNA and protein levels of 3 transglutaminase isoforms that are expressed in human brain. Overall, transglutaminase activity was significantly increased in the globus pallidus (182% of control) and pons in PSP (171% of control) but not the occipital cortex (a region spared from pathology). Using a Spearman rank correlation test, we found that tissues with more transglutaminase-activity had more neurofibrillary tangles. Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.

Aged↗

PubMed2004

Apoptosis of hippocampal neurons in organotypic slice culture models: direct effect of bacteria revisited.

Neurons of the hippocampal dentate gyrus selectively undergo programmed cell death in patients suffering from bacterial meningitis and in experimental models of pneumococcal meningitis in infant rats. In the present study, a membrane-based organotypic slice culture system of rat hippocampus was used to test whether this selective vulnerability of neurons of the dentate gyrus could be reproduced in vitro. Apoptosis was assessed by nuclear morphology (condensed and fragmented nuclei), by immunochemistry for active caspase-3 and deltaC-APP, and by proteolytic caspase-3 activity. Co-incubation of the cultures with live pneumococci did not induce neuronal apoptosis unless cultures were kept in partially nutrient-deprived medium. Complete nutrient deprivation alone and staurosporine independently induced significant apoptosis, the latter in a dose-response way. In all experimental settings, apoptosis occurred preferentially in the dentate gyrus. Our data demonstrate that factors released by pneumococci per se failed to induce significant apoptosis in vitro. Thus, these factors appear to contribute to a multifactorial pathway, which ultimately leads to neuronal apoptosis in bacterial meningitis.

Animals↗

PubMed1995

Phosphorylation of paired helical filament tau in Alzheimer's disease neurofibrillary lesions: focusing on phosphatases.

The major brain abnormalities in patients with Alzheimer's disease (AD) include extracellular deposits of beta-amyloid, intraneuronal neurofibrillary lesions, and the massive loss of specific subsets of telencephalic neurons. Neurofibrillary lesions contain paired helical filaments (PHFs) that accumulate in the perikarya (e.g., neurofibrillary tangles) and processes (e.g., dystrophic neurites, neuropil threads) of selectively vulnerable telencephalic neurons. The subunits of PHFs are derivatized forms of central nervous system (CNS) tau proteins (CNS tau) known collectively as PHFtau. Until very recently it was thought that the aberrant phosphorylation of PHFtau was the most salient difference between normal human CNS tau and PHFtau. However, this view required modification when it was shown that fetal and biopsy-derived human CNS tau proteins were phosphorylated at nearly all of the same sites found in PHFtau, albeit to a lesser extent. More significantly, these and other studies may be interpreted to suggest that the abnormal phosphorylation of PHFtau may result from the failure of protein phosphatases (i.e., PP2A and 2B) to dephosphorylate PHFtau. In this review, we summarize current understanding of the role of kinases and phosphatases in pathogenesis of PHFtau. We then consider how the formation PHFtau in neurons could disrupt the microtubule network, impair axonal transport, and compromise the viability of neurons, thereby contributing to the onset and progression of AD.

Alzheimer Disease↗

PubMed2001

Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis.

Mutations in alpha-synuclein, a protein highly enriched in presynaptic terminals, have been implicated in the expression of familial forms of Parkinson's disease (PD) whereas native alpha-synuclein is a major component of intraneuronal inclusion bodies characteristic of PD and other neurodegenerative disorders. Although overexpression of human alpha-synuclein induces dopaminergic nerve terminal degeneration, the molecular mechanism by which alpha-synuclein contributes to the degeneration of these pathways remains enigmatic. We report here that alpha-synuclein complexes with the presynaptic human dopamine transporter (hDAT) in both neurons and cotransfected cells through the direct binding of the non-A beta amyloid component of alpha-synuclein to the carboxyl-terminal tail of the hDAT. alpha-Synuclein--hDAT complex formation facilitates the membrane clustering of the DAT, thereby accelerating cellular dopamine uptake and dopamine-induced cellular apoptosis. Since the selective vulnerability of dopaminergic neurons in PD has been ascribed in part to oxidative stress as a result of the cellular overaccumulation of dopamine or dopamine-like molecules by the presynaptic DAT, these data provide mechanistic insight into the mode by which the activity of these two proteins may give rise to this process.

Apoptosis↗

PubMed1989

Effect of excitatory amino acid receptor blocker MK-801 on overall, neurologic, and morphologic outcome after prolonged cardiac arrest in dogs.

Excitatory amino acids accumulating in the brain during ischemia may cause selective neuronal damage postischemia. This hypothesis was tested in a series of studies using MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, in a reproducible outcome model of prolonged cardiac arrest in dogs. After normothermic ventricular fibrillation cardiac arrest, the dogs were resuscitated with closed-chest femoral veno-arterial cardiopulmonary bypass. At 4 h they were separated from bypass, ventilation was controlled for 20 h, and intensive care was continued to 96 h. In Study I, ventricular fibrilation cardiac arrest (no-flow) was 17 min; starting immediately with reperfusion, MK-801 1200 mg/kg (n = 5) or an equal volume of placebo (n = 5) was infused over 12 h in blinded, randomized fashion. In Study II, the duration of the no-flow period was reduced to 15 min, and MK-801 2400 mg.kg-1 (n = 4) or placebo (n = 4) was infused. In Study III, no-flow lasted for 15 min, and MK-801 2400 mg/kg was started 30 min before ventricular fibrillation (n = 4); comparison was with Study II controls. In all three studies, MK-801 plasma concentrations peaked at greater than 50 ng/ml and were 15-30 ng/ml over 12 h. All 22 dogs of experiments within protocol survived with severe brain damage. MK-801 delayed return of pupillary reactivity, EEG activity, consciousness, and respiration, necessitating longer periods of controlled ventilation. Neurologic deficit scores, overall performance categories, and brain and heart morphologic damage scores at 96 h did not differ between placebo and MK-801 pretreatment or post-treatment groups. These negative outcome results after prolonged cardiac arrest do not negate the hyperexcitability hypothesis of selective vulnerability, but suggest the existance of additional mechanisms of secondary brain damage.

Animals↗

PubMed2000

Periischemic cerebral blood flow (CBF) does not explain beneficial effects of isoflurane on outcome from near-complete forebrain ischemia in rats.

BACKGROUND: Isoflurane improves outcome from near-complete forebrain ischemia in rats compared with fentanyl-nitrous oxide (N2O). Sympathetic ganglionic blockade with trimethaphan abolishes this beneficial effect. To evaluate whether anesthesia-related differences in cerebral blood flow (CBF) may explain these findings, this study compared regional CBF before, during, and after near-complete forebrain ischemia in rats anesthetized with either isoflurane (with and without trimethaphan) or fentanyl-nitrous oxide. METHODS: Fasted, normothermic isoflurane anesthetized Sprague-Dawley rats were prepared for near-complete forebrain ischemia (10 min of bilateral carotid occlusion and mean arterial pressure = 30 mmHg). After surgery, rats were anesthetized with either 1.4% isoflurane (with or without 2.5 mg of trimethaphan intravenously at onset of ischemia) or fentanyl-nitrous oxide (25 microgram. kg-1. h-1. 70% N2O-1). Regional CBF was determined (14C-iodoantipyrine autoradiography) before ischemia, 8 min after onset of ischemia, and 30 min after onset of reperfusion. RESULTS: Regional CBF did not differ significantly among groups at any measurement interval. Ischemia caused a marked flow reduction to 5% or less of baseline (P < 0.001) in selectively vulnerable regions, such as the cortex, caudoputamen and hippocampus, whereas flow in the brain stem and cerebellum was preserved. Reperfusion at 30 min was associated with partial restoration of flow to 35-50% of baseline values in ischemic structures. CONCLUSIONS: The results indicate that improved histologic-behavioral outcome provided by isoflurane anesthesia cannot be explained by differential vasodilative effects of the anesthetic states before, during, or after severe forebrain ischemia. This study also shows severe postischemic delayed hypoperfusion that was not affected by choice of anesthetic or the presence of trimethaphan. Mechanisms other than effects on periischemic CBF must be responsible for beneficial effects of isoflurane in this model.

Anesthetics, Inhalation↗

PubMed2005

Traumatic brain injury and hemorrhagic hypotension suppress neuroprotective gene expression in injured hippocampal neurons.

BACKGROUND: After traumatic brain injury, memory dysfunction is due in part to damage to the hippocampus. To study the molecular mechanisms of this selective vulnerability, the authors used laser capture microdissection of neurons stained with Fluoro-Jade to directly compare gene expression in injured (Fluoro-Jade-positive) and adjacent uninjured (Fluoro-Jade-negative) rat hippocampal neurons after traumatic brain injury and traumatic brain injury plus hemorrhagic hypotension. METHODS: Twelve isoflurane-anesthetized Sprague-Dawley rats underwent moderate (2.0 atm) fluid percussion traumatic brain injury followed by either normotension or hemorrhagic hypotension. Animals were killed 24 h after injury. Frozen brain sections were double stained with 1% cresyl violet and 0.001% Fluoro-Jade. RNA from 10 Fluoro-Jade-positive neurons and 10 Fluoro-Jade-negative neurons, obtained from the hippocampal CA1, CA3, and dentate gyrus subfields using laser capture microdissection, was linearly amplified and analyzed by quantitative ribonuclease protection assay for nine neuroprotective and apoptosis-related genes. RESULTS: In injured CA3 neurons, expression of the neuroprotective genes glutathione peroxidase 1, heme oxygenase 1, and brain-derived neurotrophic factor was significantly decreased compared with that of adjacent uninjured neurons. Superimposition of hemorrhagic hypotension was associated with down-regulation of neuroprotective genes in both injured and uninjured neurons of all subregions. Expression of apoptosis-related genes did not vary between injured and uninjured neurons, with or without superimposed hemorrhage. CONCLUSIONS: The authors show, in the first direct comparison of messenger RNA levels in injured and uninjured hippocampal neurons, that injured neurons express lower levels of neuroprotective genes than adjacent uninjured neurons.

Animals↗

PubMed1993

Selective loss of NADPH-diaphorase-containing neurons in the dentate gyrus following transient ischemia.

The effect of transient forebrain ischemia on NADPH-diaphorase-containing neurons was examined in the dentate gyrus of the gerbil. NADPH-diaphorase histochemistry was performed in animals subjected to temporary occlusion of the common carotid arteries and sham-operated animals. Seven days following transient ischemia, the number of NADPH-diaphorase-positive neurons in the infragranular zone of the dentate gyrus was reduced by approximately 50% compared with control animals. Since neighboring granule cells are known to be resistant to this level of ischemic challenge, the present observations indicate that NADPH-diaphorase-containing neurons in the dentate gyrus are selectively vulnerable to brief ischemia.

Amino Acid Oxidoreductases↗

PubMed1995

Parvalbumin is a marker of ALS-resistant motor neurons.

The selective vulnerability of limb and bulbar motor neurons is a hallmark of degenerative human motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Currently, there are no known molecular characteristics to distinguish between motor neuron pools which are highly susceptible to degeneration in ALS and those populations which are resistant. Using in situ hybridization on adult rat tissue, we demonstrated that ALS-resistant motor pools robustly express mRNA for the calcium binding protein parvalbumin, while no measurable parvalbumin expression is found in ALS-sensitive motor neuron populations. In contrast, mRNA expression for each of several other calcium binding proteins such as calbindin-D28K, calretinin and calmodulin appears similar in the various motor pools. Thus, parvalbumin represents a biochemical marker of ALS-resistant motor neurons, and may provide insight into the mechanisms of resistance of certain motor neurons to disease.

Amyotrophic Lateral Sclerosis↗

PubMed1995

Alteration of [3H]hemicholinium-3 binding in the post-ischaemic gerbil brain.

To determine whether presynaptic sites are resistant to cerebral ischaemia, we investigated the postischaemic alteration in [3H]hemicholinium-3 binding as a sensitive marker of presynaptic cholinergic terminals in the gerbil brain between 1 h and 7 days after recirculation using receptor autoradiography. Transient ischaemia was induced for 10 min. [3H]hemicholinium-3 binding was unchanged in the frontal cortex, striatum and hippocampus throughout the recirculation periods. Our histological study revealed conspicuous neuronal damage in the frontal cortex, striatum, hippocampal CA1 sector and hippocampal CA3 sector after ischaemia. The present study demonstrates that presynaptic sites in selectively vulnerable areas can maintain their structural components although postsynaptic neurones are clearly degenerated. Thus our findings support the hypothesis that presynaptic sites are particularly resistant to ischaemia, but postsynaptic sites are vulnerable.

Animals↗

PubMed1997

Annexin V labels apoptotic neurons following hypoxia-ischemia.

The translocation of phosphatidylserine from the cytosol to the external surface of the plasma membrane has been documented as a characteristic feature of apoptosis in a number of cell types. Annexin V is a calcium-dependent phospholipid binding protein that has high affinity for phosphatidylserine. To investigate whether Annexin V provides a marker of apoptosis in the central nervous system we carried out histochemical analysis of its binding in the 21-day-old rat brain at various time-points following a moderate unilateral hypoxic-ischemic (HI) insult. The CA1 pyramidal neurons, which are selectively vulnerable to HI injury and that die by an apoptotic mechanism showed an increase in Annexin V binding 48-168 hours post-insult.

Animals↗

PubMed1999

Low expression of GluR2 AMPA receptor subunit protein by human motor neurons.

Disturbance of glutamate neurotransmission may contribute to motor neuron injury in amyotrophic lateral sclerosis. There is evidence that human motor neurons may express a specific profile of glutamate receptors, with low or absent expression of mRNA for the GluR2 AMPA receptor subunit, which has a crucial role in controlling calcium permeability. This study, using an immunocytochemical approach with a GluR2 specific antibody, shows that human upper and lower motor neurons have a very low/absent expression of GluR2 protein, in contrast to many other neuronal groups. Thus, it is likely that human motor neurons express a high proportion of atypical, calcium permeable AMPA receptors which may contribute to selective vulnerability and may allow cell-specific modulation of the actions of glutamate.

Aged↗

PubMed2002

Impairment of mitochondrial metabolism differentially affects striatal neuronal subtypes.

Electrophysiological and microfluorometric measurements were combined to analyse the responses of rat striatal medium spiny (MS) and large aspiny (LA) interneurons to the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylidrazone (FCCP). FCCP produced a membrane depolarisation coupled to an irreversible increase in intracellular calcium [Ca2+]i in MS. Conversely, LA interneurons hyperpolarised and a moderate [Ca2+]i rise was observed. Cyclosporin A, inhibitor of the mitochondrial membrane transition pore, prevented the FCCP-induced changes in LA interneurons, whereas only a partial reduction was observed in MS cells. The present results indicate that mitochondrial Ca2+ released into the cytosol may contribute to the selective vulnerability to metabolic impairment in striatal neuronal subtypes.

Animals↗

PubMed2002

Quantitative assessment of AMPA receptor mRNA in human spinal motor neurons isolated by laser capture microdissection.

Disturbance of glutamate neurotransmission may contribute to the motor neuron injury seen in amyotrophic lateral sclerosis. Previous studies have suggested that human spinal motor neurons express a specific profile of the AMPA subtype of glutamate receptor with low mRNA expression for the GluR2 AMPA receptor subunit but other studies have contested this finding. The present study uses laser capture microdissection to isolate specifically identified neurons coupled with quantitative RT-PCR to demonstrate that the level of expression of the GluR2 subunit is lower in spinal motor neurons than in dorsal horn neurons from the same spinal cord region. Thus, it is likely that human spinal motor neurons express a proportion of Ca2+-permeable AMPA receptors which may contribute to the selective vulnerability of these cells in amyotrophic lateral sclerosis.

Aged↗

PubMed1996

Content of brain aluminum is not elevated in Alzheimer disease.

Several studies have reported that the bulk aluminum (Al) concentration is increased in the brain in Alzheimer disease (AD), while other studies have failed to demonstrate an increase. Most of these investigations have had one or more methodological deficiencies, including lack of adequate neuropathological assessment; failure to age-match the control samples; small sample sizes, lacking statistical power; and geographical heterogeneity in the AD and control populations. The present population-based study of 92 clinically and histopathologically diagnosed AD patients and normal elderly nursing home residents was designed to avoid these potential biases. When a subsample of AD cases with the most severe brain pathology was compared with controls having no or minimal pathology, no statistically significant differences were found in the bulk aluminum concentration measured by graphite furnace atomic absorption spectrometry in frontal cortex (1.8 +/- 0.7 vs. 1.7 +/- 0.7 micrograms/g dry wt), temporal cortex (1.4 +/- 0.3 vs. 1.5 +/- 0.5 micrograms/g dry wt), liver (2.0 +/- 1.3 vs. 2.0 +/- 1.2 micrograms/g dry wt), or head of femur (2.4 +/- 1.6 vs. 2.2 +/- 1.0 micrograms/g ash wt). Within the whole series of 92 cases, there was no difference in the bulk aluminum concentration of the frontal cortex between individuals diagnosed as definite, probable, and possible cases of AD using the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) criteria. The density of senile plaques and neurofibrillary tangles in frontal and temporal cortex showed no correlation with the bulk aluminum concentration. Logistic regression analyses, which controlled for age and sex, did not influence outcome for any of the comparisons. The data show conclusively that in AD, bulk aluminum concentration is not increased in two cortical brain regions that are selectively vulnerable to the neuropathological changes associated with this disorder.

Aged↗