Biomedical subjects

E Masliah

Publications and source records attributed to E Masliah.

At least 127 records · Page 7Linked to original sources

PubMed1998

Novel role of human CD4 molecule identified in neurodegeneration.

The human CD4 molecule (hCD4) is expressed on T lymphocytes and macrophages and acts as a key component of the cellular receptor for HIV. At baseline, hCD4 transgenic mice expressed hCD4 on microglia, the resident mononuclear phagocytes of the brain, and showed no neuronal damage. Activation of brain microglia by peripheral immune challenges elicited neurodegeneration in hCD4 mice but not in nontransgenic controls. In post-mortem brain tissues from AIDS patients with opportunistic infections, but without typical HIV encephalitis, hCD4 expression correlated with neurodegeneration. We conclude that hCD4 may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system.

AIDS-Related Opportunistic Infections↗

PubMed1998

Expression pattern of synucleins (non-Abeta component of Alzheimer's disease amyloid precursor protein/alpha-synuclein) during murine brain development.

The non-Abeta component of Alzheimer's disease amyloid precursor protein (NACP) is predominantly a neuron-specific presynaptic protein that may play a central role in neurodegeneration because NACP fragments are found in Alzheimer's disease amyloid and a mutation in the NACP gene is associated with familial Parkinson's disease. In addition, NACP may play an important role during synaptogenesis and CNS development. To understand better the patterns of NACP expression during development, we analyzed the levels of this protein as well as the levels of another synaptic protein (synaptophysin) by ribonuclease protection assay, western blotting, and immunocytochemistry in fetal, juvenile, and adult mouse brain. From embryonic day 12 to 15, there was a slight increase, which was then followed by a more dramatic increase at later time points. Immunocytochemical staining for NACP increases throughout these stages as well. Although NACP appeared early in CNS development, synaptophysin levels started to rise at a later stage. These findings support the contention that NACP might be important for CNS development. Furthermore, the cytosolic component of NACP precedes the particulate component in development, indicating that a redistribution of the protein to the membrane fraction may be important for events later in neuronal development and in synaptogenesis.

Alzheimer Disease↗

PubMed1998

Caspase dependent DNA fragmentation might be associated with excitotoxicity in Alzheimer disease.

Recent studies have shown that deficient functioning of glutamate transporters (GTs) in Alzheimer disease (AD) might lead to neurodegeneration via excitotoxicity; however, the characteristics of cell death and pathways involved are not yet clear. The main objective of the present study was to determine if deficient GT functioning in AD could be associated with cell damage and caspase activation. For this purpose, we analyzed the levels of caspase-1 and 3 immunoreactivity in AD and control brains and correlated this data with the numbers of cells displaying DNA fragmentation, GT activity, and amyloid precursor protein (APP) mRNA expression. Compared to controls, AD cases showed extensive positive labeling of neurons and glial cells with an assay for DNA fragmentation suggestive of cell damage, as well as increased neuronal caspase-3 and Bcl-2 immunoreactivity. Linear regression analysis showed a strong negative correlation between GT activity and apoptosis, and between deficient GT functioning and caspase-3 immunoreactivity. Neurons displaying DNA fragmentation presented more intense caspase-3 immunoreactivity than intact neurons. In addition, the altered ratio between the spliced forms of APP correlated with DNA fragmentation and caspase-3 immunolabeling. Taken together, these results support the possibility that excitotoxic injury associated with deficient GT functioning and an imbalance in ratio of spliced APP forms might lead to cell death via caspase-3 activation.

ATP-Binding Cassette Transporters↗

PubMed1998

Distribution of brain HIV load in AIDS.

Approximately one quarter of patients with AIDS develop severe cognitive deficits called HIV-associated dementia complex (ADC). There is some controversy regarding the importance of viral load in mediating neurologic disease. With the advent of sensitive, quantitative and reproducible RNA assays for HIV load in plasma and CSF, we quantified viral load in brains from 10 autopsied HIV-infected subjects and 2 non-infected controls. The new quantitative HIV RNA assays showed general agreement with previously used semi-quantitative immunocytochemical assessments of HIV envelope protein, and were performed without professional subjective interpretation. All cases with very high levels of HIV in the CSF, had high overall levels in the brain, suggesting that CSF viral loads exceeding 10(6) copies per mL may be a surrogate marker of high viral load in the brain. Levels of virus in the spleen showed no clear association with those found in the brain. HIV RNA was not uniformly distributed throughout the brain. Selective regions, including basal ganglia and hippocampus, showed higher levels of virus than the cerebellar cortex and mid-frontal cortical gray matter. Assessment of overall brain viral load requires careful attention to regional quantitation.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Association of CYP2D microsatellite polymorphism with Lewy body variant of Alzheimer's disease.

OBJECTIVE: To examine the genetic association of CYP2D6 locus with Lewy body variant (LBV) and Parkinson's disease (PD). METHODS: Allelic association was studied in patients with pure AD, LBV, and PD by using the CYP2D microsatellite, the (dG-dT)n dinucleotide repeat (n=16 to 27) located between CYP2D8P and CYP2D7 genes, and the CYP2D6 B and D mutations. RESULTS: We found overrepresentation of the alleles longer than 21 repeat (the long-type alleles) in LBV (allele frequency, 0.313) (odds ratio=1.99, p=0.019 by chi2 test) and in PD (0.298) (odds ratio=1.86, p=0.037), but not in pure AD (0.196), compared with the age-matched control (0.186). Strong association was noted of the long-type alleles with the CYP2D6 B mutation (odds ratio=88.50, p < 0.001 by Fisher's exact test), but not with the D mutation or the deletion of CYP2D6 gene. CONCLUSIONS: The CYP2D locus is closely associated with LBV and PD. The CYP2D6 B mutation may be involved in pathogenesis of LBV and PD in a dominant-negative manner, or in the linkage disequilibrium of the CYP2D microsatellite to another pathogenic gene locus.

Aged↗

PubMed1998

Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders.

The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as a-synuclein) is a presynaptic terminal molecule that accumulates in the plaques of Alzheimer's disease. Recent studies have shown that a mutation in NACP is associated with familial Parkinson's disease, and that Lewy bodies are immunoreactive with antibodies against this molecule. To clarify the patterns of accumulation and differences in abnormal compartmentalization, we studied NACP immunoreactivity using double immunolabeling and laser scanning confocal microscopy in the cortex of patients with various neurodegenerative disorders. In Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease, NACP was found to immunolabel cortical Lewy bodies, abnormal neurites, and dystrophic neurites in the plaques. Double-labeling studies showed that all three of these neuropathological structures also contained ubiquitin, synaptophysin, and neurofilament (but not tau) immunoreactivity. In contrast, neurofibrillary tangles, neuropil threads, Pick bodies, ballooned neurons, and glial tangles (most of which were tau positive) were NACP negative. These results support the view that NACP specifically accumulates in diseases related to Lewy bodies such as Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease and suggests a role for this synaptic protein in the pathogenesis of neurodegeneration.

Aged↗

PubMed1998

Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment.

The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as alpha-synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, we studied NACP/alpha-synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.

Cadaver↗

PubMed1998

Neurodegenerative Alzheimer-like pathology in PDAPP 717V-->F transgenic mice.

In summary, PDAPP mice overexpressing a mutation associated with some cases of familial early-onset AD express several of the major pathological hallmarks associated with AD. Amyloid plaques in PDAPP mice appear quite similar to A beta deposits in AD as shown by a variety of different antibodies and stains, and are of both the diffuse and compacted varieties. Additionally, a subset of these amyloid plaques appear to be neuritic plaques. Neurodegenerative changes, including the loss of synaptic and dendritic proteins, abnormal phosphorylation of cytoskeletal elements, subcellular degenerative changes, and the deposition of lysosomal and acute phase proteins has also been seen in PDAPP mouse brains. Reactive astrocytosis and microgliosis have also been observed in association with the amyloid plaques in the PDAPP mice. No neurofibrillary tangles or paired helical filaments have been found in the mice to date. It remains unknown whether mice are capable of generating these in a manner comparable to AD in less than two years. Extensive behavioral analyses are currently being performed in these mice, and preliminary results indicate that the PDAPP mice are significantly impaired on a variety of different learning and memory tests. In conclusion, the PDAPP mouse model doesn't display all the pathological hallmarks of AD, but it does display most of them in a robust manner that increases with age and gene dosage. Therefore, this transgenic model provides evidence that alterations in APP processing and A beta production can result in AD-like neuropathology, can contribute to a mechanistic understanding of AD (since examination of AD brains yields a static view, and we are unable to view the development of various pathological changes), as well as providing an useful animal model for the testing of various therapeutic interventions directed towards specific aspects of the neurodegenerative process.

Alzheimer Disease↗

PubMed1997

Estrogens stimulate tamoxifen-induced neuronal cell apoptosis in vitro: a possible nongenomic action.

Estrogens are implicated in the regulation of neuronal cell death and survival in the nervous system. However, the molecular mechanisms are largely unknown. Here, we investigated effects of estrogens and an anti-estrogen compound, tamoxifen (TMX), on the death/survival of GT1-7 hypothalamic neuronal cells. Endogenous nuclear estrogen receptors (ERs) in these cells were found to be inactive on the basis of luciferase assay. Treatment of cells with TMX stimulated cell death, which was associated with DNA ladder formation characteristic of apoptosis. Both 17-beta estradiol, which stimulates ER-mediated transcription, and 17-alpha estradiol, which does not, had little effect on cell survival. Both estradiols, however, significantly potentiated TMX-induced cell death. Similar effects were obtained by estriol, but more remarkable effects were observed by quinestrol, an ethinyl estradiol derivative, which has an ether-modification at the C3 position. Furthermore, either TPA or forskolin, a potent stimulator of protein kinase C or A, respectively, also stimulated TMX-induced cell death. Taken together, these results may suggest that genomic activity through ERs is not prerequisite for estrogen stimulation of TMX-induced apoptosis, but that the cell death pathway of TMX could be modulated at the cytoplasmic level by estrogens, whose activity is dependent upon their molecular structure.

Animals↗

PubMed1997

Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease.

Deposition of amyoid-beta peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-beta peptide are not known. The transforming growth factor TGF-beta1 plays a central role in the response of the brain to injury, and increased TGF-beta1 has been found in the central nervous system of patients with Alzheimer's disease. Here we report that TGF-beta1 induces amyloid-beta deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-beta1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology, accelerated the deposition of amyloid-beta peptide. More TGF-beta1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-beta deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-beta1 may initiate or promote amyloidogenesis in Alzheimer's disease and in experimental models and so may be a risk factor for developing Alzheimer's disease.

Aged↗

PubMed1997

Reversible ischemia increases levels of Alzheimer amyloid protein precursor without increasing levels of mRNA in the rabbit spinal cord.

In a rabbit spinal cord ischemia model (RSCIM), the time courses of neuropathological damage of the spinal cord and neurological impairment of the motor functions are well established, demonstrating that the extent of neuropathological damage and the severity of neurological impairment are closely correlated. We used the RSCIM to elucidate the effects of reversible (15 min) and irreversible (60 min) ischemia on the endogenous levels of amyloid protein precursors (APPs) at both the mRNA and protein levels in the caudolumbar/sacral region of the spinal cord. We speculate that endogenous APPs are induced by ischemia as either trophic factors or stress-induced proteins in the RSCIM. A 15-min occlusion transiently increased the APP protein levels in neurons, which returned to the original levels by the end of 60 min occlusion. The increase in APP protein levels during 15-min ischemic insult does not appear to involve regulation at the mRNA level. The increased level of APPs, particularly of the soluble form, could support the possibility that APPs play a neuroprotective role in the RSCIM as stress-induced proteins. In contrast, failure to maintain the increased APP protein levels or to increase the mRNA, as seen in the 60-min ischemia samples, may be one of the causal factors that induce necrosis and neuronal cell death leading to irreversible neurological impairment.

Amyloid beta-Protein Precursor↗

PubMed1997

NACP, a synaptic protein involved in Alzheimer's disease, is differentially regulated during megakaryocyte differentiation.

Non-amyloid-beta component precursor (NACP) is a presynaptic protein which may play a role in amyloidogenesis in Alzheimer's disease (AD). Since an abnormal function of platelets has been demonstrated in AD, platelets could be used as a model to investigate the role of NACP in this disease. We characterized the patterns of NACP and beta-synuclein expression in a megakaryocyte-platelet system (K562). In this hematopoietic cell line, NACP expression was up-regulated during phorbol ester-induced megakaryocytic differentiation, while beta-synuclein was down-regulated. Consistent with this, NACP but not beta-synuclein was abundantly expressed in platelets. Immunogold electron microscopy of platelets showed that NACP is loosely associated with the plasma membrane, the endomembrane system and, occasionally, with the membrane of secretory alpha-granules. These findings suggest that coordinate expression of the synuclein family members may play a critical role during hematopoietic cell differentiation. Additionally, expression of the synuclein family members may be developmentally regulated during neural differentiation.

Amyloid↗

PubMed1997

Neurodegeneration and cognitive impairment in apoE-deficient mice is ameliorated by infusion of recombinant apoE.

Recent studies suggest that apolipoprotein E (apoE) might play a neurotrophic function in the central nervous system and that altered functioning of this molecule could result in neurodegeneration. The main objective of this study was to determine if neurodegenerative and cognitive alterations in apoE-deficient mice are reversible by infusion of recombinant apoE into the lateral ventricles. ApoE-deficient mice treated with either apoE3 or apoE4 showed a significant improvement in their learning capacity in the Morris water maze compared to saline-infused apoE-deficient mice. While this improved performance was associated with restoration of neuronal structure, the poor learning ability of apoE-deficient mice treated with saline correlated with the disrupted synapto-dendritic structure. This study supports the contention that apoE might play a neurotrophic effect in vivo and suggests that apoE might have a potential therapeutic role.

Animals↗

PubMed1997

Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain.

Inflammation with expression of interleukin 6 (IL-6) in the brain occurs in many neurodegenerative disorders. To better understand the role of IL-6 in such disorders, we examined performance in a learning task in conjunction with molecular and cellular neuropathology in transgenic mice that express IL-6 chronically from astrocytes in the brain. Transgenic mice exhibited dose- and age-related deficits in avoidance learning that closely corresponded with specific progressive neuropathological changes. These results establish a link between the central nervous system expression of IL-6, inflammatory neurodegeneration, and a learning impairment in transgenic mice. They suggest a critical role for a proinflammatory cytokine in the cognitive deficits and associated neuroinflammatory changes that have been documented in neurodegenerative diseases such as Alzheimer disease and AIDS.

Age Factors↗

PubMed1997

Genetic evidence for the involvement of tau in progressive supranuclear palsy.

A dinucleotide repeat polymorphism in a tau intron was identified and used in a case-control study to analyze the genetic association of tau with several neurodegenerative diseases with tau pathology. Subjects with the homozygous tau AO alleles were excessively represented in the progressive supranuclear palsy (PSP) group, compared with the age-matched healthy control group. Consequently, this allele is more frequently found in PSP than in a group of healthy subjects. This trend was not found in Alzheimer's disease or parkinsonism-dementia complex of Guam, both of which are accompanied by major tau pathology. The result suggests a possible involvement of tau in the pathogenesis of PSP.

Base Sequence↗

PubMed1997

Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC Group. The HIV Neurobehavioral Research Center.

To determine the neuropathological substrate of human immunodeficiency virus (HIV)-associated neurocognitive disorders, we examined persons with acquired immunodeficiency syndrome before their death and related their antemortem neuropsychological performance to postmortem indicators of HIV encephalitis, viral burden, and presynaptic and postsynaptic neuronal injury. Of 20 prospectively examined cases, 9 were neurocognitively normal, 5 showed neuropsychological impairment, 5 had minor cognitive/motor disorder, and 1 was demented. Degree of neurocognitive impairment was strongly related to the amount of dendritic simplification based on microtubule-associated protein 2 immunohistochemical staining, somewhat less so to a semiquantitative viral burden score based on numbers of HIV gp41-immunoreactive cells, and much less so to the presence of multinucleated giant cells or microglial nodules. It appears that even milder neurocognitive impairment reflects microneuroanatomical injury to synaptic structures.

AIDS-Related Opportunistic Infections↗

PubMed1997

Lesions in the dentate hilum and CA2/CA3 regions of the rat hippocampus produce cognitive deficits that correlate with site-specific glial activation.

Thirty male rats pressed a lever three times (FR3) when a stimulus light (sD) was off to obtain sucrose pellets. They were then evenly divided into sham Controls versus groups lesioned bilaterally in the hippocampus by stercotaxic injection of ibotenic acid into the dentate hilum (HIL) or the CA2/CA3 region (CA2/3). On measures of recall of the FR3-sD task taken during the initial 30 min of a postlesion test session, the CA2/3 and especially the HIL groups showed significant (p < .05) impairments relative to the Controls. During an ensuing 30-min period, rats were reshaped to criterion, beginning at FR1, and no appreciable intergroup differences were noted on this schedule or at FR1-sD. At FR2-sD, the HIL but not the CA2/3 group showed some impairment relative to Controls. At FR3-sD, both the CA2/3 and HIL groups had impaired task performance. An immunocytochemical index of glial activation showed higher reactivity in CA2/3 or the dentate hilum among CA2/3 or HIL animals, respectively, that was associated with the degree to which they showed an FR3-sD performance deficit.

Animals↗

PubMed1997

Neurofibrillary tangles in the dentate granule cells of patients with Alzheimer's disease, Lewy body disease and progressive supranuclear palsy.

Recent studies have shown that the dentate granular cells of the hippocampus are affected in patients with Alzheimer's disease (AD). To gain a better understanding of the cytoskeletal alterations in these cells, we carried out immunocytochemical and immunoelectron microscopic analysis of the dentate gyrus of patients with primary degenerative dementias, using a monoclonal antibody against paired helical filaments (TG3). This antibody labeled a large number of spherical inclusions in the dentate granule cells of patients with AD and its Lewy body variant (LBV). These inclusions consisted of straight tubular structures (about 18-25 nm in diameter), similar to those found in progressive supranuclear palsy (PSP). These inclusions, although in a smaller number, were also found in demented patients with PSP, but not in those with diffuse Lewy body disease or age-matched controls. These findings indicate that the neurofibrillary alterations in the dentate granule cells of patients with AD, LBV and PSP share cytoskeletal similarities.

Alzheimer Disease↗