Neurocytopathic effects of beta-amyloid-stimulated monocytes: a potential mechanism for central nervous system damage in Alzheimer disease.

Growing evidence indicates that cells of the mononuclear phagocyte lineage, which includes peripheral blood monocytes (PBM) and tissue macrophages, participate in a variety of neurodestructive events and may play a pivotal role in neurodegenerative conditions such as Alzheimer disease. The present study sought to determine whether exposure of PBM to beta-amyloid peptide (A beta), the major protein of the amyloid fibrils that accumulate in the brain in Alzheimer disease, could induce cytopathic activity in these cells upon their subsequent incubation with neural tissue. PBM were incubated with A beta for 3 days, centrifuged and washed to remove traces of cell-free A beta, and then applied to organotypic cultures of rat brain for varying periods of time. By using a cell-viability assay to quantitate neurocytopathic effect, an increase in the ratio of dead to live cells was detected in cultures containing A beta-stimulated PBM versus control PBM (stimulated with either bovine serum albumin or reverse A beta peptide) as early as 3 days after coculture. The ratio of dead to live cells increased further by 10 days of coculture. By 30 days of coculture, the dead to live cell ratio remained elevated, and the intensity of neurocytopathic effect was such that large areas of brain mass dissociated from the cultures. These results indicate that stimulation of PBM with A beta significantly heightens their neurocytopathic activity and highlight the possibility that inflammatory reactions in the brain play a role in the neurodegeneration that accompanies Alzheimer disease.

Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis.

The CBFA2 (AML1) gene encodes a DNA-binding subunit of the heterodimeric core-binding factor. The CBFA2 gene is disrupted by the (8;21), (3;21), and (12;21) chromosomal translocations associated with leukemias and myelodysplasias in humans. Mice lacking a CBF alpha 2 protein capable of binding DNA die between embryonic days 11.5 and 12.5 due to hemorrhaging in the central nervous system (CNS), at the nerve/CNS interfaces of cranial and spinal nerves, and in somitic/intersomitic regions along the presumptive spinal cord. Hemorrhaging is preceded by symmetric, bilateral necrosis in these regions. Definitive erythropoiesis and myelopoiesis do not occur in Cbfa2-deficient embryos, and disruption of one copy of the Cbfa2 gene significantly reduces the number of progenitors for erythroid and myeloid cells.

Fine specificity of the antibody response to myelin basic protein in the central nervous system in multiple sclerosis: the minimal B-cell epitope and a model of its features.

T cells, B cells, and antibody are found in the white matter of the central nervous system in multiple sclerosis. The epitope center for the antibody response to human myelin basic protein (MBP) fits precisely the minimal epitope Pro85-Val-Val-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro96 for that reported for HLA DR2b (DRB1*1501)-restricted T cells that recognize MBP [Wucherpfenning, K.W., Sette, A., Southwood, S., Oseroff, C., Matsui, M., Strominger, J. & Hafler, D. (1994) J. Exp. Med. 179, 279-290], and overlaps with the reported DR2a-restricted epitope for T cells reactive to MBP [Martin, R., Howell, M. D., Jaraquemada, D., Furlage, M., Richert, J., Brostoff, S., Long, E. O., McFarlin, D. E. & McFarland, H. F. (1991) J. Exp. Med. 173, 19-24]. We describe a molecular model of this epitope.

Unimpaired autoreactive T-cell traffic within the central nervous system during tumor necrosis factor receptor-mediated inhibition of experimental autoimmune encephalomyelitis.

The critical role of tumor necrosis factor (TNF) as a mediator in autoimmune inflammatory processes is evident from in vivo studies with TNF-blocking agents. However, the mechanisms by which TNF, and possibly also its homologue lymphotoxin alpha, contributes to development of pathology in rheumatoid arthritis and Crohn disease and in animal models like experimental autoimmune encephalomyelitis is unclear. Possibilities include regulation of vascular adhesion molecules enabling leukocyte movement into tissues or direct cytokine-mediated effector functions such as mediation of tissue damage. Here we show that administration of a TNF receptor (55 kDa)-IgG fusion protein prevented clinical signs of actively induced experimental autoimmune encephalomyelitis. Significantly, the total number of CD4+ T lymphocytes isolated from the central nervous system of clinically healthy treated versus diseased control animals was comparable. By using a CD45 congenic model of passively transferred experimental autoimmune encephalomyelitis to enable tracking of myelin basic protein-specific effector T lymphocytes, prevention of clinical signs of disease was again demonstrated in treated animals but without quantitative or qualitative impediment to the movement of autoreactive T lymphocytes to and within the central nervous system. Thus, despite the uninterrupted movement of specific T lymphocytes into the target tissue, subsequent disease development was blocked. This provides compelling evidence for a direct effector role of TNF/lymphotoxin alpha in autoimmune tissue damage.

Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha.

Cytokines are now recognized to play important roles in the physiology of the central nervous system (CNS) during health and disease. Tumor necrosis factor alpha (TNF-alpha) has been implicated in the pathogenesis of several human CNS disorders including multiple sclerosis, AIDS dementia, and cerebral malaria. We have generated transgenic mice that constitutively express a murine TNF-alpha transgene, under the control of its own promoter, specifically in their CNS and that spontaneously develop a chronic inflammatory demyelinating disease with 100% penetrance from around 3-8 weeks of age. High-level expression of the transgene was seen in neurons distributed throughout the brain. Disease is manifested by ataxia, seizures, and paresis and leads to early death. Histopathological analysis revealed infiltration of the meninges and CNS parenchyma by CD4+ and CD8+ T lymphocytes, widespread reactive astrocytosis and microgliosis, and focal demyelination. The direct action of TNF-alpha in the pathogenesis of this disease was confirmed by peripheral administration of a neutralizing anti-murine TNF-alpha antibody. This treatment completely prevented the development of neurological symptoms, T-cell infiltration into the CNS parenchyma, astrocytosis, and demyelination, and greatly reduced the severity of reactive microgliosis. These results demonstrate that overexpression of TNF-alpha in the CNS can cause abnormalities in nervous system structure and function. The disease induced in TNF-alpha transgenic mice shows clinical and histopathological features characteristic of inflammatory demyelinating CNS disorders in humans, and these mice represent a relevant in vivo model for their further study.

A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury.

Within the central nervous system (CNS) ciliary neurotrophic factor (CNTF) is expressed by astrocytes where it remains stored as an intracellular protein; its release and function as an extracellular ligand are thought to occur in the event of cellular injury. We find that overexpression of CNTF in transgenic mice recapitulates the glial response to CNS lesion, as does its injection into the uninjured brain. These results demonstrate that CNTF functions as an inducer of reactive gliosis, a condition associated with a number of neurological diseases of the CNS.

Local nitric oxide production in viral and autoimmune diseases of the central nervous system.

Because of the short half-life of NO, previous studies implicating NO in central nervous system pathology during infection had to rely on the demonstration of elevated levels of NO synthase mRNA or enzyme expression or NO metabolites such as nitrate and nitrite in the infected brain. To more definitively investigate the potential causative role of NO in lesions of the central nervous system in animals infected with neurotropic viruses or suffering from experimental allergic encephalitis, we have determined directly the levels of NO present in the central nervous system of such animals. Using spin trapping of NO and electron paramagnetic resonance spectroscopy, we confirm here that copious amounts of NO (up to 30-fold more than control) are elaborated in the brains of rats infected with rabies virus or borna disease virus, as well as in the spinal cords of rats that had received myelin basic protein-specific T cells.

Managing atypical and typical herpetic central nervous system infections: results of a multinational study

There have been many studies pertaining to the management of herpetic meningoencephalitis (HME), but the majority of them have focussed on virologically unconfirmed cases or included only small sample sizes. We have conducted a multicentre study aimed at providing management strategies for HME. Overall, 501 adult patients with PCR-proven HME were included retrospectively from 35 referral centres in 10 countries; 496 patients were found to be eligible for the analysis. Cerebrospinal fluid (CSF) analysis using a PCR assay yielded herpes simplex virus (HSV)-1 DNA in 351 patients (70.8%), HSV-2 DNA in 83 patients (16.7%) and undefined HSV DNA type in 62 patients (12.5%). A total of 379 patients (76.4%) had at least one of the specified characteristics of encephalitis, and we placed these patients into the encephalitis presentation group. The remaining 117 patients (23.6%) had none of these findings, and these patients were placed in the nonencephalitis presentation group. Abnormalities suggestive of encephalitis were detected in magnetic resonance imaging (MRI) in 83.9% of the patients and in electroencephalography (EEG) in 91.0% of patients in the encephalitis presentation group. In the nonencephalitis presentation group, MRI and EEG data were suggestive of encephalitis in 33.3 and 61.9% of patients, respectively. However, the concomitant use of MRI and EEG indicated encephalitis in 96.3 and 87.5% of the cases with and without encephalitic clinical presentation, respectively. Considering the subtle nature of HME, CSF HSV PCR, EEG and MRI data should be collected for all patients with a central nervous system infection.

Course of lectures on the physiology and pathology of the central nervous system : delivered at the Royal college of surgeons of England in May, 1858 /

Includes bibliographical references and index.

The threat of predictable and unpredictable pain: Differential effects on central nervous system processing?

Central nervous system performance is disrupted by pain and by the threat of pain. It is not known whether disruption caused by the threat of pain is dependent on the likelihood of pain occurring. We hypothesised that when a painful stimulus is possible but unpredictable central nervous system performance is reduced, but when the pain is predictable and unavoidable it is not. Sixteen healthy subjects performed a reaction time task during predictable and unpredictable conditions (100% and 50% probability of pain, respectively). Group data showed increased reaction time with the threat of pain by 50 ms (95% Cl 16 to 83 ms) for the predictable condition and 46 ms (95% CI 12 to 80 ms) for the unpredictable condition (p < 0.01 for both), but there was no difference between predictable and unpredictable conditions (p = 0.41). However, individual data showed that there was a differential effect in 75% of subjects (p < 0.05 for all) and that there was a greater effect of predictable pain for some subjects and a greater effect of unpredictable pain for others. Reaction time was related to reported anxiety (r = 0.49, p = 0.02 for both conditions). The predictability of a painful stimulus may have a differential effect on central nervous system performance within individuals, but anxiety about the impending pain appears to be important in determining this effect.

In vivo and in vitro aspects of imidazoline-2(1/2)sites within the central nervous system

The in vivo and in vitro characteristics of the I2 binding site were probed using the technique of drug discrimination and receptor autoradiography. Data presented in this thesis indicates the I2 ligand 2-BFI generates a cue in drug discrimination. Further studies indicated agmatine, a proposed endogenous imidazoline ligand, and a number of imidazoline and imidazole analogues of 2-BFI substitute significantly for 2-BFI. In addition to specific I2 ligands the administration of NRl's (noradrenaline reuptake inhibitors), the sympathomimetic d-amphetamine, the α1-adrenoceptor agonist methoxamine, but not the β1 agonist dobutamine or the β2 agonist salbutamol, gave rise to significant levels of substitution for the 2-BFI cue. The administration of the α1-adrenoceptor antagonist WB4101, prior to 2- BFI itself significantly reduced levels of 2-BFI appropriate responding. Administration of the reversible MAO-A inhibitors moclobemide and Ro41-1049, but not the reversible MAO-B inhibitors lazabemide and Ro16-6491, gave rise to potent dose dependent levels of substitution for the 2-BFI cue. Further studies indicated the administration of a number of β-carbolines and the structurally related indole alkaloid ibogaine also gave rise to dose dependent significant levels of substitution. Due to the relationship of indole alkaloids to serotonin the 5-HT releaser fenfluramine and a number of SSRI's (selective serotonin reuptake inhibitor) were also administered and these compounds gave rise to significant partial (20-80% responses to the 2-BFI lever) levels of substitution. The autoradiographical studies reported here indicate [3H]2-BFI labels I2 sites within the rat arcuate nucleus, area postrema, pineal gland, interpeduncular nucleus and subfornical organ. Subsequent experiments confirmed that the drug discrimination dosing schedule significantly increases levels of [3H]2-BFI 12 binding within two of these nuclei. However, levels of [3H]2-BFI specific binding were significantly reduced within four of these nuclei after chronic treatment with the irreversible MAO inhibitors deprenyl and tranylcypromine but not pargyline, which only reduced levels significantly in two. Further autoradiographical studies indicated that the distribution of [3H]2-BFI within the C57/B mouse compares favourably to that within the rat. Comparison of these levels of binding to those from transgenic mice who over-express MAO-B indicates two possibly distinct populations of [3H]2-BFI 12 sites exist in mouse brain. The data presented here indicates the 2-BFI cue is associated with the selective activation of α1-adrenoceptors and possibly 5-HT receptors. 2-BFI trained rats recognise reversible MAO-A but not MAO-B inhibitors. However, data within this thesis indicates the autoradiographical distribution of I2 sites bears a closer resemblance to that of MAO-B not MAO-A and further studies using transgenic mice that over-express MAO-B suggests a non-MAO-B I2 site exists in mouse brain.