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Biomedical subjects

E Masliah

Publications and source records attributed to E Masliah.

At least 145 records · Page 8Linked to original sources
PubMed1997

Alterations in glutamate receptor 2/3 subunits and amyloid precursor protein expression during the course of Alzheimer's disease and Lewy body variant.

Alterations in the processing and patterns of trophic and/or toxic factors might lead to the increased neuronal vulnerability in the entorhinal cortex in Alzheimer's disease (AD) and Lewy body variant (LBV). Therefore, patterns and levels of amyloid precursor protein (APP) and glutamate receptor (gluR) expression in the entorhinal cortex and hippocampus in relation to disease severity were investigated. Sections from the hippocampus and entorhinal cortex were single and double immunolabeled for APP, gluR2/3, and N-methyl-D-aspartate receptor (NMDA-R). Within the hippocampus and entorhinal cortex, image analysis revealed progressively decreased APP and gluR2/3 levels during the course of AD and LBV, whereas levels of NMDA-R were unaltered. Furthermore, the present study showed a positive correlation and close co-localization of APP and gluR2/3 immunoreactivity in neurons, suggesting a possible interaction between these two factors. In conclusion, these data imply that alterations in neuronal APP and gluR2/3 expression in the entorhinal cortex lead to increased susceptibility to neurodegeneration and might be markers of vulnerability.

Alzheimer Disease↗
PubMed1997

Subpial vacuolar myelopathy after intrathecal ketamine: report of a case.

Previous studies of intrathecal ketamine use in humans have documented the clinical effects of its administration without reference to local central nervous system (CNS) toxicity (Reich and Silvay, 1989). Although several post-mortem studies in small groups of rabbits, monkeys, and baboons have largely shown no significant CNS damage after intrathecal ketamine use, a study in rats reported vacuolation of dorsal root ganglia (Ahuja, 1983). We report post-mortem CNS histopathological changes of subpial spinal cord vacuolation in a terminally ill cancer patient who received continuous infusion intrathecal ketamine at a rate of 5 mg/day for a duration of 3 weeks.

Anesthetics, Intravenous↗
PubMed1997

Amyloid precursor proteins protect neurons of transgenic mice against acute and chronic excitotoxic injuries in vivo.

The beta-amyloid protein precursor (APP) is well conserved across different species and may fulfill important physiological functions within the CNS. While high-level neuronal expression of amyloidogenic forms of human APP results in beta-amyloid production and neurodegeneration, lower levels of neuronal human APP expression in neurons of transgenic mice may primarily accentuate physiological functions of this molecule. To assess the neuroprotective potential of human APP in vivo, mice from seven distinct transgenic lines expressing different human APP isoforms from the neuron-specific enolase promoter were challenged with systemic kainate injections (n=30) or transgene-mediated glial expression of gp120 (n=32), an HIV-1 protein capable of inducing excitotoxic neuronal damage. To quantitate human APP-mediated neuroprotection. the area of neuropil occupied by presynaptic terminals and neuronal dendrites in the neocortex and hippocampus of each mouse was determined using laser scanning confocal microscopy of double-immunolabelled brain sections and computer-aided image analysis. Compared with gp120 singly transgenic controls, mice from three of three human APP751gp120 bigenic lines expressing the 751 amino acid form of human APP at low levels showed significant protection against degeneration of presynaptic terminals; two of these lines also showed significantly less damage to neuronal dendrites. Two of three human APP695/gp120 bigenic lines expressing human APP695 at low levels were protected against presynaptic and dendritic damage, whereas one low expressor line and a human APP695/gp120 bigenic line expressing human APP695 at higher levels showed no significant protection. In the corresponding human APP singly transgenic lines, overexpressing only specific human APP isoforms, significant protection against kainate-induced degeneration of presynaptic terminals and neuronal dendrites was found in two of three human APP751 lines and not in any of the four human APP695 lines tested. These results indicate that human APP can protect neurons against chronic and acute excitotoxic insults in vivo and that human APP isoforms differ in their neuroprotective potential, at least with respect to specific forms of neural injury. It is therefore possible that impairments of neuroprotective human APP functions or aberrant shifts in human APP isoform ratios could contribute to neurodegeneration.

Amyloid beta-Protein Precursor↗
PubMed1997

Transgenic models to assess the pathogenic actions of cytokines in the central nervous system.

In order to better understand the actions of proinflammatory cytokines in the mammalian CNS, a transgenic approach was employed in which the expression of IL-6, IL-3 or TNF-alpha was targeted to astrocytes in the intact CNS of mice. Transgenic mice exhibited distinct chronic-progressive neurological disorders with neurodegeneration and cognitive decline due to IL-6 expression, macrophage/microglial-mediated primary demyelination with motor impairment due to IL-3 expression and lymphocytic meningoencephalomyelitis with paralysis induced by TNF-alpha expression. Thus, expression of specific cytokines alone in the intact CNS results in unique neuropathological alterations and functional impairments, thereby directly implicating these mediators in the pathogenesis of CNS disease.

Animals↗
PubMed1997

Neurodegeneration of somatostatin-immunoreactive neurons in HIV encephalitis.

Recent studies have suggested that neuronal populations that contain glutamate receptors are vulnerable to damage mediated by the human immunodeficiency virus 1 (HIV-1). Somatostatin-immunoreactive neurons contain, among other elements, glutamate receptors, and might therefore be susceptible to HIV-mediated damage. In order to test this hypothesis, we compared patterns of somatostatin immunoreactivity in the cortex and subcortex of autopsied AIDS cases with and without HIV encephalitis (HIVE). Somatostatin immunoreactivity in the frontal cortex interneurons, hippocampal pyramidal and nonpyramidal cells, and globus pallidus was significantly reduced in HIVE. Radioimmunoassay demonstrated a comparable decrease in somatostatin levels in the neocortex of HIVE cases. The decrease in somatostatin immunoreactivity in the neocortex was inversely correlated with the severity of HIVE and global cognitive performance, but not with the extent of the astroglial reaction. These findings indicate that somatostatin-immunoreactive neurons in the cortex are susceptible to damage mediated by HIV and that deficient functioning of this neuronal population might contribute to the cognitive dysfunction observed in AIDS patients.

Basal Ganglia↗
PubMed1997

Glutamate transporter alterations in Alzheimer disease are possibly associated with abnormal APP expression.

Recent studies have shown that deficient functioning of glutamate transporters (GTs) in Alzheimer disease (AD) might lead to neurodegeneration. The main objectives of the present study were to determine which GT subtype is most affected in AD and to asses to what extent altered GT function is associated with abnormal amyloid precursor protein (APP) expression. While EAAT2-immunoreactivity (IR) was decreased in AD frontal cortex, EAAT1- and EAAT3-IR were unaffected; mRNA levels for all 3 GTs were not affected. Decreased EAAT2-IR was associated with decreased GT activity. EAAT2-IR inversely correlated with EAAT2 mRNA levels, suggesting that in AD, GT expression alterations occur due to disturbance at the post-transcriptional level. EAAT2-IR was inversely correlated with APP770 mRNA. In addition, GT activity directly correlated with APP695 mRNA and total APP protein levels, and inversely correlated with APP751/770 mRNA levels. This study supports the notion that astroglial EAAT2 is affected in AD and abnormal functioning and/or processing of APP might play an important role in this process.

ATP-Binding Cassette Transporters↗
PubMed1997

Comparison of two quantitative methods for the evaluation of neuronal number in the frontal cortex in Alzheimer disease.

How to assess the substantial neuronal loss in a neurodegenerative disease such as Alzheimer disease is still being debated. Recently, stereological procedures have been proposed that claim improved accuracy and statistical power, but the results of some of these investigations have been controversial. In this study we compared and correlated the cell density results calculated per unit of volume obtained by a stereological technique, the "selector," with the cell counts per unit area obtained by computer-aided image analysis morphometry, in the same sections of midfrontal cortex in Alzheimer disease and control cases. The "selector" revealed a significant decrease in neuronal density that correlated well with a similar fall in large neuronal counts per unit area, as estimated by image analysis morphometry. These results indicate that stereological techniques and image analysis morphometry are complementary methods in reliably assessing cellular populations in neurodegenerative disorders.

Aged↗
PubMed1997

Glial cells in Alzheimer's disease: preferential effect of APOE risk on scattered microglia.

Reactive glial cells are consistently found in the brain tissue of Alzheimer's disease (AD) patients. Both clustered and scattered glial cells occur in AD brain. A number of clustered microglial cells, but not astrocytes, had a positive correlation with neurite plaque numbers, suggesting that clustered micro-glial cells are uniquely associated with plaques whereas clustered astrocytes may have functions outside the plaques as well. APOE epsilon 4, the major genetic risk factor for AD, had a dose-dependent effect to increase the numbers of scattered microglial cells whereas the APOE risk showed no correlation with any of the clustered glial cells or scattered astrocytes. These findings raise the possibility that the increased levels of scattered, but not clustered, microglial cells are the immediate response to APOE risk and might be primarily involved in AD pathogenesis.

Aged↗
PubMed1997

Hippocampal sclerosis contributes to dementia in the elderly.

OBJECTIVE: To assess the relevance of hippocampal sclerosis (HS) to dementia in the elderly. BACKGROUND: HS is a prominent pathologic finding in some demented elderly, but the anatomic substrate and cognitive profiles of this dementia have not been well established. DESIGN/METHODS: An autopsy series, including dot-immunobinding assay to estimate neocortical synaptic density, of eight patients (three men, five women) with HS on whom extensive antemortem neuropsychological testing was available. RESULTS: Mean age at onset was 72.0 (+/-9.8) (range, 59 to 89) with a mean duration of symptoms of 6.5 (+/-2.9) years. Patients were only mildly impaired with a mean MMSE of 20.9 (+/-4.9) and a mean DRS of 103.1 (+/-12.5) at presentation. Cardiovascular disease was present in 88%, with a mean Hachinski score of 3.4 (+/-2.2). No patient had a history of seizures. Sixty-three percent had depression or depressive symptoms. Neuropsychologically, most patients presented with prominent memory and language deficits and became progressively demented. Neuropathologically, isolated HS was a rare finding; many patients had either very mild or neocortical "plaque only or plaque predominant" Alzheimer's disease (AD) in addition to HS changes. Midfrontal neocortical synaptophysin counts were significantly reduced in all HS patients compared with controls (p = 0.0006). CONCLUSIONS: In the elderly, HS can be a neuropathologic substrate of dementia. Clinically, it can be associated with a course that is difficult to distinguish from AD although cardiac disease and depression are frequent concomitants. Deterioration of cognitive function in these subjects may relate to other pathologic features such as neocortical synapse loss.

Aged↗
PubMed1997

Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease.

The presence of the APOE epsilon 4 allele encoding apolipoprotein E4 (apoE4) is the major genetic risk factor for late-onset Alzheimer's disease (AD). However, the molecular and cellular mechanisms by which APOE epsilon 4 renders AD risk are unclear. In this report, we present genetic evidence that an apoE receptor, LRP, may be associated with the expression of late-onset AD. Using a biallelic genetic marker in exon 3 of LRP, late-onset AD cases markedly differed from the control subjects in the distribution of LRP genotypes, and this difference was highly accentuated among AD cases with positive family history of senile dementia. Furthermore, the numbers of neutritic plaques were significantly altered as a consequence of different LRP genotypes in postmortem AD cases. Taken together, our results implicate the pathophysiology of LRP in the expression of late-onset AD.

Age of Onset↗
PubMed1996

Detection of borna disease virus antigen and RNA in human autopsy brain samples from neuropsychiatric patients.

Borna disease virus (BDV) causes a central nervous system disease in several vertebrate species which is characterized by behavioral disturbances. Seroepidemiological data indicate an association of BDV infection with certain human mental disorders. Sclerosis of the hippocampus and astrocytosis constitute histopathological hallmarks of BDV infection in animals. Therefore, we searched for human brain autopsy cases with such histopathological features. Five of 600 cases examined were identified as having hippocampus sclerosis and astrocytosis. Using immunocytochemistry, RT-PCR, and in situ hybridization, we detected both BDV antigen and RNA in autopsy brain samples from 4 of these 5 patients, who presented with a clinical history of mental disorders involving memory loss and depression. This is the first demonstration that BDV can infect human brain tissue, possibly contributing to the pathophysiology of specific human neuropsychiatric disorders.

Animals↗
PubMed1996

Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease.

Overexpression of mutated human amyloid precursor protein (hAPP717V-->F) under control of platelet-derived growth factor promoter (PDAPP minigene) in transgenic (tg) mice results in neurodegenerative changes similar to Alzheimer's disease (AD). To clarify the pathology of these mice, we studied images derived from laser scanning confocal and electron microscopy and performed comparisons between PDAPP tg mice and AD. Similar to AD, neuritic plaques in PDAPP tg mouse contained a dense amyloid core surrounded by anti-hAPP- and antineurofilament-immunoreactive dystrophic neurites and astroglial cells. Neurons were found in close proximity to plaques in PDAPP tg mice and, to a lesser extent, in AD. In PDAPP tg mice, and occasionally in AD, neuronal processes contained fine intracellular amyloid fibrils in close proximity to the rough endoplasmic reticulum, coated vesicles, and electron-dense material. Extracellular amyloid fibrils (9-11 nm in diameter) were abundant in PDAPP tg and were strikingly similar to those observed in AD. Dystrophic neurites in plaques of PDAPP tg mouse and AD formed synapses and contained many dense multilaminar bodies and neurofilaments (10 nm). Apoptotic-like figures were present in the tg mice. No paired helical filaments have yet been observed in the heterozygote PDAPP tg mice. In summary, this study shows that PDAPP tg mice develop massive neuritic plaque formation and neuronal degeneration similar to AD. These findings show that overproduction of hAPP717V-->F in tg mice is sufficient to cause not only amyloid deposition, but also many of the complex subcellular degenerative changes associated with AD.

Alzheimer Disease↗
PubMed1996

Isoform-specific redistribution of protein kinase C in living cells.

We have used confocal laser scanning microscopy to determine the dynamics of distribution of activated protein kinase C (PKC) in living Madin Darby canine kidney (MDCK) cells. Using fluorescently tagged phorbol myristate acetate (PMA) as a probe for PKC we have demonstrated its distribution in association with the cell periphery and with the nucleus. Dual labeling experiments using PKC alpha and PKC beta II specific antisera indicate that activated PKC alpha is found in association with the periphery whereas activated PKC beta II is translocated to the nucleus. We have demonstrated increased activity of PKC in nuclear fractions isolated from cells treated with PMA and other PKC activators. These data indicate that upon activation individual isoforms of PKC translocate to different subcellular locations where they are likely to mediate different actions.

Animals↗
PubMed1996

Viral persistence in neurons alters synaptic plasticity and cognitive functions without destruction of brain cells.

Neurons have a restricted expression of MHC heavy chain molecules which prevents presentation of antigens of infecting viruses. As a result, such infected cells escape immune surveillance and allow the establishment of noncytolytic persistent infection. Here we show that a chronic noncytolytic viral infection both in vitro and in vivo selectively perturbed the expression of GAP-43, a protein that plays a central role in neuronal plasticity processes accompanying learning and memory. GAP-43 expression was greatly decreased in the hippocampus, an area of heightened viral replication, while synaptic density was preserved. Concurrently, the ability to learn tasks was significantly impaired in these persistently infected mice. Yet, infected neurons remained free from structural injury.

Animals↗
PubMed1996

The synaptic protein NACP is abnormally expressed during the progression of Alzheimer's disease.

NACP, the precursor of non-A beta component of Alzheimer's disease (AD) amyloid (NAC), is a synaptic protein that could potentially be involved in AD. We studied, by dot-blot, NACP levels in the frontal cortex of AD cases staged according to severity of disease and correlated them with cognitive performance and neuropathological markers. Early AD cases showed one fold higher levels of NACP immunoreactivity (IR) compared to moderate and severe AD. Levels of NACP-IR were correlated with tangle counts (r = -0.305, P = 0.04) and Blessed score (r = -0.356, P = 0.01), but not with plaque counts (r = 0.132, P = 0.39). This study suggests that the abnormal accumulation of NACP during the early stages of AD might play an important role in the mechanisms of neurodegeneration and synaptic damage in AD.

Aged↗
PubMed1996

Dysregulation of signal transduction pathways as a potential mechanism of nervous system alterations in HIV-1 gp120 transgenic mice and humans with HIV-1 encephalitis.

HIV-1 associated central nervous system (CNS) disease involves neuronal damage and prominent reactive astrocytosis, the latter characterized by strong upregulation of the glial fibrillary acidic protein (GFAP) in astrocytes. Similar alterations are found in transgenic mice expressing the HIV-1 envelope protein gp120 in the CNS. Because alterations of astrocyte functions could contribute to neuronal impairment, we compared brains of gp120 transgenic mice and gp120-transfected C6 astrocytoma cells with controls and found that gp120 induced a prominent elevation of steady state GFAP mRNA levels, primarily due to transcript stabilization. Increased levels of GFAP mRNA were also found in nontransfected C6 cells exposed to recombinant gp120. Exposure of C6 cells or primary mouse astrocytes to soluble gp120 led to activation of PKC as indicated by redistribution and increase in PKC immunoreactivity at the single cell level. gp120 effects were diminished by inhibitors of protein kinase C (PKC) but not inhibitors of protein kinase A. PKC activity was upmodulated in gp120-transfected C6 cells and in the CNS of gp120 transgenic mice. Further, brain tissue from patients with HIV-1 encephalitis and from gp120 transgenic mice showed increased PKC immunoreactivity. Taken together, these results indicate that gp120-induced increases in PKC activity may contribute to the gliosis seen in gp120 transgenic mice as well as in HIV-1-infected humans and raise the question of whether dysregulation of signal transduction pathways represents a general mechanism of HIV-associated pathogenesis.

AIDS Dementia Complex↗
PubMed1996

Neurotrophic and neuroprotective effects of hAPP in transgenic mice.

To better understand the role the human amyloid precursor protein (hAPP) plays in Alzheimer's disease (AD), it is essential to define its primary function(s). Here we expressed different hAPPs in neurons of transgenic (tg) mice to characterize their effects on the intact central nervous system (CNS). Immunolabeled brain sections of tg and non-tg mice were compared quantitatively by microdensitometry and computer-aided analysis of laser scanning confocal digitized images. Compared with non-tg mice, tg mice overexpressing hAPPs showed an increase in the number of synaptophysin immunoreactive presynaptic terminals as well as in the expression of the growth-associated marker GAP-43. While non-tg controls and tg mice expressing hAPP751 at moderate levels displayed a normal pattern of reinnervation of the dentate gyrus following perforant pathway transection, tg mice expressing hAPP695 at severalfold higher levels showed an accentuation of the synaptic loss and no sprouting reaction. In addition, expression of hAPP751 at moderate levels effectively protected neurons against excitotoxic injury induced either acutely by systemic injection of kainic acid or chronically by transgene-driven glial production of the soluble HIV-1 protein gp120. Neuronal expression of hAPP695 at higher levels provided less excitoprotection. Our findings are consistent with the postulate that APP plays a role in the formation/maintenance of synapses and that processes which affect this function could contribute to the synaptic pathology seen in AD. Our study also revealed that hAPPs can exert important excitoprotective functions in vivo and that the efficiency of this protection may depend on the hAPP isoform expressed as well as on the level of neuronal hAPP expression. Neuronal overexpression of hAPP beyond a certain level may have detrimental effects on the CNS, particularly in the context of secondary neural injuries.

Amyloid beta-Protein Precursor↗