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PubMed2001

Locally reduced levels of acidic FGF lead to decreased expression of 28-kda calbindin and contribute to the selective vulnerability of the neurons in the entorhinal cortex in Alzheimer's disease.

Recent studies demonstrate that a disturbed calcium-homeostasis leading to increased susceptibility to excitotoxic triggers plays a major role in the neurodegenerative process initiating in layer 2 of the entorhinal cortex (EC2) during Alzheimer's disease (AD). Thus, proteins binding free Ca++ (i.e. calbindin) and factors regulating these proteins are of great importance for the neuroprotective-neurotoxic balance in the affected brain regions. In the present combined human and in vitro study evidence is provided that altered levels of the acidic fibroblast growth factor (aFGF) and calbindin expression are concomitantly present in EC2 neurons and have interactive effects. A dramatic loss of aFGF- and calbindin-labeled EC2 neurons was found. Further analysis of the surviving EC2 neurons revealed a strong immunoreactivity to calbindin and aFGF. In vitro experiments show that aFGF regulates calbindin expression, because treatment of differentiating neurons with recombinant aFGF increases calbindin expression in a time-dependent fashion. The data imply that a reduced expression of aFGF in EC2 neurons of AD brains leads to lower levels of calbindin resulting in decreased neuroprotective capacity.

Aged↗
PubMed1999

Differences in the activation of the mitochondrial permeability transition among brain regions in the rat correlate with selective vulnerability.

Mitochondria from different regions of the brain were prepared, and the activation of the mitochondrial permeability transition (MPT) by calcium was investigated by monitoring the associated mitochondrial swelling. In general, the properties of the MPT in brain mitochondria were found to be qualitatively similar to those observed in liver and heart mitochondria. Thus, swelling was inhibited by adenine nucleotides (AdNs) and low pH (<7.0), whereas thiol reagents and alkalosis facilitated swelling. Cyclosporin A and its nonimmunosuppressive analogue N-methyl-Val-4-cyclosporin A (PKF 220-384) both inhibited swelling and prevented the translocation of cyclophilin D from the matrix to the membranes of cortical mitochondria. However, the calcium sensitivity of the MPT differed in mitochondria from three brain regions (hippocampus > cortex > cerebellum) and is correlated with the susceptibility of these regions to ischemic damage. Depleting mitochondria of AdNs by treatment with pyrophosphate ions sensitized the MPT to [Ca2+] and abolished regional differences, implying regional differences in mitochondrial AdN content. This was confirmed by measurements showing significant differences in AdN content among regions (cerebellum > cortex > hippocampus). Our data add to recent evidence that the MPT may be involved in neuronal death.

Adenine Nucleotides↗
PubMed1995

Selective vulnerability of late-generated dopaminergic neurons of the substantia nigra in weaver mutant mice.

In homozygous weaver (wv/wv) mutant mice, nearly 50% of the dopaminergic substantia nigra neurons degenerate by postnatal day 20. We have now determined that the total number of dopaminergic neurons in the ventral midbrains of a litter of obligatory homozygous weaver pups and a litter of normal wild-type control pups indicates that no significant differences are present between groups at birth. To test the hypothesis that the subsequent degeneration of these neurons is linked to their time of origin, [3H]thymidine autoradiography was combined with tyrosine hydroxylase immunocytochemistry to construct neurogenetic timetables on postnatal day 20 in wild-type mice and weaver homozygotes. Both groups have the same span of neurogenesis but have statistically different proportions of neurons generated on specific days. In wild-type mice, more than half of the dopaminergic neurons originate on or after embryonic day 12. In contrast, over two-thirds of the surviving dopaminergic neurons in homozygous weaver mice originate on or before embryonic day 11. Our data suggest that the weaver gene does not interfere with the generation of dopaminergic neurons, but it preferentially kills late-generated dopaminergic neurons between birth and postnatal day 20.

Aging↗
PubMed2004

Cortical selective vulnerability in motor neuron disease: a morphometric study.

Neuroimaging and neuropsychological studies have revealed that the primary motor cortex (PMC) and the extramotor cortical areas are functionally abnormal in motor neuron disease (MND, amyotrophic lateral sclerosis), but the nature of the cortical lesions that underlie these changes is poorly understood. In particular, there have been few attempts to quantify neuronal loss in the PMC and in other cortical areas in MND. We used SMI-32, an antibody against an epitope on non-phosphorylated neurofilament heavy chain, to analyse the size and density of SMI-32-positive cortical pyramidal neurons in layer V of the PMC, the dorsolateral prefrontal cortex (DLPFC) and the supragenual anterior cingulate cortex (ACC) in 13 MND and eight control subjects. There was a statistically significant reduction in the density of SMI-32-immunoreactive (IR) pyramidal neurons within cortical layer V in the PMC, the DLPFC and the ACC in MND subjects compared with controls [t (19) = 2.91, P = 0.009; estimated reduction 25%; 95% CI = 8%, 40%]. In addition, we studied the density and size of interneurons immunoreactive for the calcium-binding proteins calbindin-D(28K) (CB), parvalbumin (PV) and calretinin (CR) in the same areas (PMC, DLPFC and ACC). Statistically significant differences in the densities of CB-IR neurons were observed within cortical layers V (P = 0.003) and VI (P = 0.001) in MND cases compared with controls. The densities of CR- and PV-IR neurons were not significantly different between MND and control cases, although there were trends towards reductions of CR-IR neuronal density within the same layers and of PV-IR neuronal density within cortical layer VI. Loss of pyramidal neurons and of GABAergic interneurons is more widespread than has been appreciated and is present in areas associated with neuroimaging and cognitive abnormalities in MND. These findings support the notion that MND should be considered a multisystem disorder.

Aged↗
PubMed2004

Striatal cells from mutant huntingtin knock-in mice are selectively vulnerable to mitochondrial complex II inhibitor-induced cell death through a non-apoptotic pathway.

Extensive striatal neuronal loss occurs in Huntington's disease (HD), which is caused by an expanded polyglutamine tract in huntingtin (htt). Evidence suggests that mutant htt directly or indirectly compromises mitochondrial function, contributing to the neuronal loss. To determine the role of compromised mitochondrial function in the neuronal cell death in HD, immortalized striatal cells established from Hdh(Q7) (wild-type) and Hdh(Q111) (mutant) mouse knock-in embryos were treated with 3-nitropropionic acid (3-NP), a mitochondrial complex II toxin. 3-NP treatment caused significantly greater cell death in mutant striatal cells compared with wild-type cells. In contrast, the extent of cell death induced by rotenone, a complex I inhibitor, was similar in both cell lines. Although evidence of apoptosis was present in 3-NP-treated wild-type striatal cells, it was absent in 3-NP-treated mutant cells. 3-NP treatment caused a greater loss of mitochondrial membrane potential (deltapsim) in mutant striatal cells compared with wild-type cells. Cyclosporine A, an inhibitor of mitochondrial permeability transition pore (PTP), and ruthenium red, an inhibitor of the mitochondrial calcium uniporter, both rescued mutant striatal cells from 3-NP-induced cell death and prevented the loss of deltapsim. These data show that mutant htt specifically increases cell vulnerability to mitochondrial complex II inhibition and further switched the type of cell death induced by complex II inhibition from apoptosis to a non-apoptotic form, caused by mitochondrial membrane depolarization, probably initiated by mitochondrial calcium overload and subsequent PTP opening. These findings suggest that impaired mitochondrial complex II function in HD may contribute to non-apoptotic neuronal cell death.

Animals↗
PubMed1995

Late neuropsychological outcomes in preterm infants of normal IQ: selective vulnerability of the visual system.

Evaluated neuropsychological outcomes in 635 children, ages 7 to 10 years, in relation to birth weight group: < or = 1,000 g; 1,001-1,500 g; 1,501-2,500 g, and > 2,500 g. The prevalence of low IQ (< 85) was related to birth weight. Among children with IQ > 84 (N = 475): (a) Birth weight was unrelated to Verbal IQ, Performance IQ, Full-scale IQ, or reading achievement; (b) extremely low birth weight (ELBW) children achieved more poorly in mathematics than did other birth weight groups (p < .05); (c) ELBW and very low birth weight children performed more poorly on the Rey-Osterrieth Complex Figure, a complex visual processing task, than did heavier birth weight children (p < .05), but performance on the Beery Test of Visuomotor Integration was not related to birth weight. Results are consistent with heightened neurobehavioral vulnerability of visual processing to preterm birth.

Child↗
PubMed2000

Selective vulnerability of spinal cord motor neurons to non-NMDA toxicity.

We previously reported that alpha-motor neurons in organotypic cultures of rat spinal cord (OTC-SC) are resistant to excitotoxicity induced through NMDA receptors. Here we describe the effects of non-NMDA glutamate receptor agonists kainic acid (KA) and quisqualic acid (QUIS) on motor neurons in OTC-SC. Large ventral horn acetylcholinesterase-positive neurons (VHANs), most of which are motor neurons, were quite sensitive to QUIS and KA toxicity and displayed losses of 95% and 94%, respectively. Small VHANs were reduced by 41% and 61% only. Identical results were obtained in cultures stained for non-phosphorylated neurofilaments. These observations demonstrate that alpha-motor neurons are considerably more sensitive to KA and QUIS than to NMDA toxicity. The proposed excitotoxic mechanism of ALS, therefore, is most likely mediated through non-NMDA glutamate receptors.

Acetylcholinesterase↗
PubMed1998

Oligodendrocytes and microglia are selectively vulnerable to combined hypoxia and hypoglycemia injury in vitro.

The major classes of glial cells, namely astrocytes, oligodendrocytes, and microglial cells were compared in parallel for their susceptibility to damage after combined hypoxia and hypoglycemia or hypoxia alone. The three glial cell types were isolated from neonatal rat brains, separated, and incubated in N2/CO2-gassed buffer-containing glucose or glucose substitutes, 2-deoxyglucose or mannitol (both nonmetabolizable sugars). The damage to the cells after 6 hours' exposure was determined at 0, 1, 3, 7 days based on release of lactate dehydrogenase and counting of ethidium bromide-stained dead cells, double-stained with cell-type specific markers. When 2-deoxyglucose replaced glucose during 6 hours of hypoxia, both oligodendrocytes and microglia rarely survived (18% and 12%, respectively). Astroglia initially increased the release of lactate dehydrogenase but maintained 98% to 99% viability. When mannitol, a radical scavenger and osmolarity stabilizer, replaced glucose during 6 hours of hypoxia, oligodendrocytes rarely survived (10%), astroglia survival remained at 99%, but microglia survival increased to 50%. After exposure to 6 and 42 hours, respectively, of hypoxic conditions alone, oligodendrocytes exhibited 10% survival whereas microglia and astroglia were only temporarily stressed and subsequently survived. In conclusion, oligodendrocytes, then microglia, are the most vulnerable glial cell types in response to hypoxia or hypoglycemia conditions, whereas astrocytes from the same preparations recover.

Animals↗
PubMed1998

Selective vulnerability of the developing brain to lead.

Environmental lead exposure in young children who ingest household paint dust or other sources impairs their potential intelligence in a linear, dose-dependent fashion in contrast to its far more subtle effects on other neurologic functions. Basic investigations have identified three interrelated steps in synaptic neurotransmission at which low levels of lead can disrupt signal processing. Lead enhances background transmitter release, but impairs stimulated release, inhibits function at the N-methyl-D-aspartate-type glutamate receptor and stimulates background levels of the intracellular messenger protein kinase C. Taken together these effects have the effect of diminishing the synaptic signal to noise ratio. The ability of lead to enhance 'synaptic noise' during a critical early period of postnatal development may permanently disrupt the architecture of cortical processing units by depriving them of high resolution environmental signals needed to refine synaptic connections.

Adolescent↗
PubMed1987

Altered mitochondrial respiration in selectively vulnerable brain subregions following transient forebrain ischemia in the rat.

Mitochondrial respiratory function, assessed from the rate of oxygen uptake by homogenates of rat brain subregions, was examined after 30 min of forebrain ischemia and at recirculation periods of up to 48 h. Ischemia-sensitive regions which develop extensive neuronal loss during the recirculation period (dorsal-lateral striatum, CA1 hippocampus) were compared with ischemia-resistant areas (paramedian neocortex, CA3 plus CA4 hippocampus). All areas showed reductions (to 53-69% of control) during ischemia for oxygen uptake rates determined in the presence of ADP or an uncoupling agent, which then recovered within 1 h of cerebral recirculation. In the ischemia-resistant regions, oxygen uptake rates remained similar to control values for at least 48 h of recirculation. After 3 h of recirculation, a significant decrease in respiratory activity (measured in the presence of ADP or uncoupling agent) was observed in the dorsal-lateral striatum which progressed to reductions of greater than 65% of the initial activity by 24 h. In the CA1 hippocampus, oxygen uptake rates were unchanged for 24 h, but were significantly reduced (by 30% in the presence of uncoupling agent) at 48 h. These alterations parallel the development of histological evidence of ischemic cell change determined previously and apparently precede the appearance of differential changes between sensitive and resistant regions in the content of high-energy phosphate compounds. These results suggest that alterations of mitochondrial activity are a relatively early change in the development of ischemic cell death and provide a sensitive biochemical marker for this process.

Adenosine Diphosphate↗
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↗
PubMed1989

Selective vulnerability of pigmented dopaminergic neurons in Parkinson's disease.

From a neuropathological point, the diagnosis of Parkinson's disease is confirmed by a neuronal cell loss and the presence of Lewy bodies in the substantia nigra. In Parkinson's disease, the precise type of nigral neuron which degenerate still remains unknown. Are all types of neuron similarly injured, are only subpopulations of neurons vulnerable? In an attempt to answer the question, a qualitative and quantitative analysis of the distribution of dopaminergic cells, as identified by immunohistochemistry with a specific antibody against tyrosine hydroxylase, was performed in the ventral mesencephalon of control subjects and patients who died with a clinical diagnosis of Parkinson's disease. In control brains, two types of catecholaminergic neurons were evidenced; some contain visible-neuromelanin, others do not. In patients with Parkinson's disease, the tyrosine hydroxylase positive cells which contained the pigment were the most vulnerable.

Humans↗
PubMed1985

Ischaemia-induced injury in glycogen-depleted skeletal muscle. Selective vulnerability of FG-fibres.

The effect of preischaemic glycogen-depletion on the development of skeletal muscle injury was investigated in rats subjected to tourniquet hind-limb ischaemia. Glycogen depletion was performed by direct electrical stimulation of the extensor digitorum longus (EDL) muscle during ischaemic conditions. The metabolite load during the subsequent 2.5 h of ischaemia was modified by allowing, or not allowing, a short reperfusion period after termination of the electrical stimulation. The extent of injury was evaluated morphologically after 5 or 15 h of reperfusion, by the combination of an intravital dye exclusion test and a histochemical staining, demonstrating calcium-precipitates-Alizarin red S. Minimal damage was found in animals subjected to ischaemia without preceding glycogen depletion. In both groups of preischaemically glycogen-depleted animals, significant irreversible injury occurred. The injury was significantly less in animals in which a wash-out period was allowed after termination of stimulation. Fast-glycogenolytic fibres (FG) were most sensitive to the ischaemic insult during both experimental conditions, while slow-oxidative fibres (SO) were spared. Fast-oxidative-glycogenolytic fibres (FOG) showed an intermediate response. The injury seemed to be established after 5 h of reperfusion, indicating that cells react with an all-or-nothing response in the present model.

Animals↗