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Biomedical subjects

E Masliah

Publications and source records attributed to E Masliah.

At least 37 records · Page 2Linked to original sources
PubMed2003

Changing patterns in the neuropathogenesis of HIV during the HAART era.

Rapid progress in the development of highly active antiretroviral therapy has changed the observed patterns in HIV encephalitis and AIDS-related CNS opportunistic infections. Early in the AIDS epidemic, autopsy studies pointed to a high prevalence of these conditions. With the advent of nucleoside reverse transcriptase inhibitors, the prevalence at autopsy of opportunistic infections, such as toxoplasmosis and progressive multifocal leukoencephalopathy, declined while that of HIV encephalitis increased. After the introduction of protease inhibitors, a decline in both HIV encephalitis and CNS opportunistic infections was observed. However, with the increasing resistance of HIV strains to antiretrovirals, there has been a resurgence in the frequency of HIV encephalitis and HIV leukoencephalopathy. HIV leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy is characterized by massive infiltration of HIV infected monocytes/macrophages into the brain and extensive white matter destruction. This condition may be attributable to interactions of anti-retrovirals with cerebrovascular endothelium, astroglial cells and white matter of the brain. These interactions may lead to cerebral ischemia, increased blood-brain barrier permeability and demyelination. Potential mechanisms of such interactions include alterations in host cell signaling that may result in trophic factor dysregulation and mitochondrial injury. We conclude that despite the initial success of combined anti-retroviral therapy, more severe forms of HIV encephalitis appear to be emerging as the epidemic matures. Factors that may contribute to this worsening include the prolonged survival of HIV-infected patients, thereby prolonging the brain's exposure to HIV virions and proteins, the use of increasingly toxic combinations of poorly penetrating drugs in highly antiretroviral-experienced AIDS patients, and selection of more virulent HIV strains with higher replication rates and greater virulence in neural tissues.

AIDS Dementia Complex↗
PubMed2002

Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis.

OBJECTIVE: To investigate the value of antemortem cognitive functioning in predicting postmortem evidence of HIV encephalitis (HIVE). METHODS: Thirty-nine subjects were assessed during life with a comprehensive neuropsychological battery and went on to autopsy within 18 months of testing. Cognitive impairment was determined by blind clinical ratings, based on demographically corrected test scores. Presence of HIVE was based on postmortem immunocytochemical detection of the viral protein gp41 or by measurement of HIV RNA by PCR in multiple brain areas as well as by histopathologic evidence such as microgliosis, presence of multinucleated giant cells, and myelin pallor in several brain regions. RESULTS: The sensitivity and specificity of neurocognitive impairment in detecting the occurrence of HIVE were 67 and 92%. Eighteen of 19 subjects with antemortem neurocognitive impairment had evidence of HIV-related brain disease (positive predictive value = 95%). CONCLUSION: Neuropsychological assessment can help select HIV-positive patients for treatment of CNS disease.

AIDS Dementia Complex↗
PubMed2002

Analysis of result variability from high-density oligonucleotide arrays comparing same-species and cross-species hybridizations.

There exists a significant limitation in the variety of organismsfor which microarrays have been developed because of a lack of genomic sequence data. A near-term solution to this limitation is to use microarrays designed for one species to analyze RNA samples from closely related species. The assumption is that conservation of gene sequences between species will be sufficient to generate a reasonable amount of good-quality data. While there have been relatively few published reports describing the use of microarrays for cross-species hybridizations, this technique is potentially a powerful tool for understanding genomics in model organisms such as nonhuman primates. Here we describe the analysis and comparison of hybridization characteristics and data variability from a set of cross-species (rhesus macaque) and same-species (human) hybridization experiments using human high-density Affymetrix oligonucleotide arrays. The data reveal that a large fraction of probe sets are effective at transcript detection in the cross-species hybridization, validating the application of cross-species hybridizations for nonhuman primate genomics research.

Analysis of Variance↗
PubMed2002

Effects of Cerebrolysin on amyloid-beta deposition in a transgenic model of Alzheimer's disease.

We investigated the potential mechanisms through which Cerebrolysin, a neuroprotective noothropic agent, might affect Alzheimer's disease pathology. Transgenic (tg) mice expressing mutant human (h) amyloid precursor protein 751 (APP751) cDNA under the Thy-1 promoter (mThy1-hAPP751) were treated for four weeks with this compound and analyzed by confocal microscopy to asses its effects on amyloid plaque formation and neurodegeneration. In this model, amyloid plaques in the brain are found much earlier (beginning at 3 months) than in other tg models. Quantitative computer-aided analysis with anti-amyloid-beta protein (A beta) antibodies, revealed that Cerebrolysin significantly reduced the amyloid burden in the frontal cortex of 5-month-old mice. Furthermore, Cerebrolysin treatment reduced the levels of A beta(1-42). This was accompanied by amelioration of the synaptic alterations in the frontal cortex of mThy1-hAPP751 tg mice. In conclusion, the present study supports the possibility that Cerebrolysin might have neuroprotective effects by decreasing the production of A beta(1-42) and reducing amyloid deposition.

Alzheimer Disease↗
PubMed2001

Cholinergic deficits in the brains of patients with parkinsonism-dementia complex of Guam.

Patients with parkinsonism-dementia complex (PDC) of Guam showed moderate loss of choline acetyl transferase activity in the midfrontal and inferior parietal cortex, and severe loss in the superior temporal cortex. This deficit was similar to that seen in Alzheimer's disease and less severe than Lewy body disease. Thus, cholinergic deficits in the neocortex might contribute to some of the cognitive alterations in PDC of Guam.

Acetylcholine↗
PubMed2001

beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor.

We characterized beta-synuclein, the non-amyloidogenic homolog of alpha-synuclein, as an inhibitor of aggregation of alpha-synuclein, a molecule implicated in Parkinson's disease. For this, doubly transgenic mice expressing human (h) alpha- and beta-synuclein were generated. In doubly transgenic mice, beta-synuclein ameliorated motor deficits, neurodegenerative alterations, and neuronal alpha-synuclein accumulation seen in halpha-synuclein transgenic mice. Similarly, cell lines transfected with beta-synuclein were resistant to alpha-synuclein accumulation. halpha-synuclein was coimmunoprecipitated with hbeta-synuclein in the brains of doubly transgenic mice and in the double-transfected cell lines. Our results raise the possibility that beta-synuclein might be a natural negative regulator of alpha-synuclein aggregation and that a similar class of endogenous factors might regulate the aggregation state of other molecules involved in neurodegeneration. Such an anti-amyloidogenic property of beta-synuclein might also provide a novel strategy for the treatment of neurodegenerative disorders.

Animals↗
PubMed2001

Altered expression of the synuclein family mRNA in Lewy body and Alzheimer's disease.

The main objective of this study was to determine if levels of alpha-, beta- and/or gamma-synuclein mRNAs are differentially affected in brains of Lewy body disease (LBD) and Alzheimer's disease (AD) patients, compared to controls. In control cases, highest levels of expression were observed in the neocortex and the lowest in basal ganglia and substantia nigra. beta-Synuclein was the most abundant message (75-80%), followed by gamma-synuclein (10-15%) and alpha-synuclein (8-10%). Analysis of the superior temporal cortex, a region selectively affected in LBD and AD, showed that compared to controls, levels of alpha-synuclein were increased in cases of diffuse LBD (DLBD), levels of beta-synuclein were decreased in AD and DLBD, and levels of gamma-synuclein were increased in AD cases. This study suggests that a critical balance among products of the synuclein gene is important to maintain normal brain function and that alterations in this balance might be associated with neurodegenerative disorders.

Aged↗
PubMed2001

beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease.

Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of beta-amyloid and alpha-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human beta-amyloid peptides, alpha-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before alpha-synuclein singly tg mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more alpha-synuclein-immunoreactive neuronal inclusions than alpha-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in alpha-synuclein singly tg mice. beta-Amyloid peptides promoted aggregation of alpha-synuclein in a cell-free system and intraneuronal accumulation of alpha-synuclein in cell culture. beta-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of alpha-synuclein and exacerbating alpha-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of beta-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.

Age Factors↗
PubMed2001

Synucleins in ocular tissues.

Synucleins are small proteins associated with neurodegenerative diseases and some forms of cancer. Most studies of this group of proteins have been directed to the elucidation of their role in the brain and their connection to the formation of depositions in brain tissues. Here we describe the localization of different types of synucleins in ocular tissues. By Western blot analysis, all members of the synuclein family are found in the retina and optic nerve, where their relative ratio varies. The data on immunohistochemical staining show that different members of the synuclein family have different localizations in ocular tissues. Alpha-synucleins and beta-synucleins are present predominantly in the inner plexiform layer, whereas gamma-synuclein is in the nerve fiber layer. In transgenic mice overexpressing alpha-synuclein, a different pattern of localization depending on the promoter used for the expression was observed. In Alzheimer's disease patients, immunohistochemical staining for gamma-synuclein revealed the loss of immunoreactivity in the nerve fiber layer and the nerve fiber layer and the appearance of immunopositive cells in or near the outer nuclear layer. We conclude that, in mature eyes, synucleins are present predominantly in the retina and optic nerve, and the immunoreactivity of gamma-synuclein changes specifically in the retina of Alzheimer's disease patients. In transgenic mice overexpressing alpha-synuclein, immunopositive deposits in the optic nerve and accumulation of immunoreactivity in specific retinal cells were found.

Aged↗
PubMed2001

Altered expression of glutamate transporters under hypoxic conditions in vitro.

Regulation of extracellular excitotoxins by glial and neuronal glutamate transporters is critical to maintain synaptic terminal integrity. Factors interfering with the normal functioning of these transporters might be involved in neurodegeneration. Among them, recent studies have shown that hypoxia alters glutamate transporter function; however, it is unclear if hypoxia has an effect on the expression of glutamate transporters and which intracellular signaling pathways are involved. The C6 rat glial and GT1--7 mouse neuronal cell lines were exposed to hypoxic conditions (5% CO(2), 95% N(2)) and levels of glutamate transporter mRNA were determined by ribonuclease protection assay. After 21 hr, there was a 100% increase in levels of rat excitatory amino acid transporter 3 (EAAT3) mRNA in C6 cells and a 600% increase in levels of murine EAAT2 mRNA in GT1--7 cells. There was a similar increase in mRNA levels after hypoxia in C6 cells transfected with human EAAT2, whereas reoxygenation normalized the expression levels of glutamate transporters. Although the expression of EAATs was associated with increased immunoreactivity by Western blot, functioning of the transporters was decreased as evidenced by D-aspartate uptake. Finally, although the protein kinase C stimulator phorbol-12-myristate-13-acetate enhanced EAAT2 mRNA levels after hypoxia, protein kinase C inhibitor bisindolylmaleimide I had the opposite effect. Taken together, this study suggests that the hypoxia is capable of upregulating levels of EAATs via a protein kinase C-dependent compensatory mechanism. This increased expression is not sufficient to overcome the decreased functioning of the EAATs associated with decreased ATP production and mitochondrial dysfunction.

Amino Acid Transport System X-AG↗
PubMed2001

Blockade of PKC epsilon activation attenuates phorbol ester-induced increase of alpha-secretase-derived secreted form of amyloid precursor protein.

The role of PKC epsilon in amyloid precursor protein (APP) processing was investigated using APP-overexpressing B103 cells. As reported previously, a PKC activator, phorbol-12,13-dibutyrate (PDBu), enhanced secretion of APP alpha, and this effect was blocked by a PKC inhibitor, GF109203X in this system. Selective inhibition of PKC epsilon by overexpressing the PKC epsilon V1 region, which binds specifically to the receptor for activated C-kinase (RACK), blocked PDBu-induced enhancement of APP alpha secretion as well as PDBu-induced decrease in beta-secretase-derived APP C-terminal fragment production. On the other hand, the level of PKC epsilon, but not that of PKC alpha or PKC gamma, was substantially lower in the brains of Alzheimer's disease patients compared to age-matched controls. These results add to a growing body of evidence that PKC epsilon plays an important role in modulating APP processing, and suggest that reduced PKC epsilon activity may contribute to the development of Alzheimer's disease.

Alzheimer Disease↗
PubMed2001

Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease.

The expression levels of three synaptic proteins (synaptophysin, synaptotagmin, and growth-associated protein 43 [GAP43]) in AD cases clinically classified by Clinical Dementia Rating (CDR) score were analyzed. Compared with control subjects (CDR = 0), mild (early) AD (CDR = 0.5 to 1) cases had a 25% loss of synaptophysin immunoreactivity. Levels of synaptotagmin and GAP43 were unchanged in mild AD, but cases with CDR of >1 had a progressive decrement in these synaptic proteins. Thus, synaptic injury in frontal cortex is an early event in AD.

Aged↗
PubMed2001

Partial caudal duplication in a newborn associated with meningomyelocele and complex heart anomaly.

BACKGROUND: Caudal duplication is a spectrum of rare congenital anomalies with a possible heterogeneous pathogenesis including incomplete separation of monovular twins. METHODS: We report an autopsy case of a full-term infant with incomplete caudal duplication syndrome associated with multiple anomalies. RESULTS: These anomalies included a duplicated penis; double urinary bladder with an attenuated tunica muscularis; duplication of lower bowel with two ilia, appendices and colons; colonic hypogangliosis and left imperforated anus associated with rectourethral fistula. Other anomalies consisted of sacral meningomyelocele, sacral duplication with hypoplastic left sacrum and pelvic bones, muscle atrophy and hypoplasia of the left lower extremity, abnormal lobation of liver with stomach entrapment, omphalocele, and right atrial isomerism syndrome. The complex pattern of anomalies suggests the possibility that partial caudal duplication might be part of the spectrum of conjoined twinning.

Abnormalities, Multiple↗
PubMed2001

Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia.

Dementia lacking distinctive histopathology (DLDH) or frontotemporal lobe degeneration (FTLD) is the most common neuropathological diagnosis for sporadic frontotemporal dementias (FTDs). The hallmarks of DLDH are neuron loss and gliosis in the absence of any disease-specific brain lesion. Similar brain pathology is also seen in a familial FTD pedigree known as hereditary dysphasic disinhibition dementia 2 (HDDD2). Abnormality in the function or isoform composition of the microtubule binding protein tau is a prominent feature in the brains of many patients with sporadic and hereditary FTDs. Therefore, we studied the tau protein in different brain regions from DLDH and HDDD2 patients. Our results indicate that a selective loss of all six tau isoforms, but not tau mRNA, occurs in these brains compared to normal control and Alzheimer's disease brains. Loss of tau protein was identified by Western blot analysis of protein extracts from DLDH and HDDD2 brains in regions both with and without neuronal degeneration. Functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene identified in familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). Thus, DLDH and HDDD2 are novel tauopathies with a unique mechanism of pathogenesis. The presence of tau mRNA in these brains suggests that the level of tau protein may be controlled posttranscriptionally, at the level of either translation or mRNA stability.

Aged↗
PubMed2001

Role of apolipoprotein E receptors in regulating the differential in vivo neurotrophic effects of apolipoprotein E.

Apolipoprotein E (apoE) is known to bind to at least five receptors, including the low-density lipoprotein (LDL) receptor-related protein (LRP), very low density LDL receptor (VLDL-R), LDL-R, apoE receptor 2 (apoER2), and megalin/gp330. In this context, the main objective of the present study was to better understand the contributions of LRP and LDL-R to the in vivo neurotrophic effects of apoE. For this purpose, apoE-deficient and receptor-associated protein (RAP)-deficient mice were infused with recombinant apoE3, RAP, or saline. Infusion of apoE3 into apoE-deficient mice resulted in amelioration of degenerative alterations of pyramidal neurons, but had no effect on somatostatin-producing interneurons. In contrast, infusion of apoE3 into RAP-deficient mice resulted in amelioration of degenerative alterations of somatostatin-producing interneurons. LRP and LDL-R levels were significantly reduced in RAP-deficient mice, but significantly increased in the apoE-deficient mice. In contrast, levels of apoE were reduced in the RAP-deficient mice compared to wildtype controls, suggesting that neurotrophic effects of apoE3 in the RAP-deficient mice were related to a combined deficit in endogenous apoE and selected apoE receptors. Furthermore, in apoE-deficient mice, infusion of apoE3 had a neurotrophic effect on somatostatin-producing interneurons only when combined with RAP, suggesting that increased expression of apoE receptors in apoE-deficient mice prevented apoE from rescuing somatostatin-producing neurons. This study supports the contention that some of the in vivo neurotrophic effects of apoE are mediated by LRP and LDL-R and that a critical balance between levels of apoE and its receptors is necessary for the differential neurotrophic effects to appear.

Animals↗
PubMed2001

Reduced neuritic outgrowth and cell adhesion in neuronal cells transfected with human alpha-synuclein.

Since recent reports have suggested that alpha-synuclein might play a role in neuronal plasticity, the main objective of this study was to determine the effects of alpha-synuclein on neuritic outgrowth. We stably transfected either human (h) alpha- or beta-synuclein cDNA in B103 rat neuronal cells. Expression of h(alpha)-synuclein resulted in reduced neurite extension and weak adhesion compared to vector-transfected and h(beta)-synuclein expressing cells. To investigate the potential pathways involved, we studied the effects of reagents known to modulate B103 proliferation and differentiation. Neither phorbol 12-myristate 13-acetate nor forskolin or antioxidants (catalase, superoxide dismutase, or vitamin E) were able to restore the reduced length of neurites in h(alpha)-synuclein-expressing cells. These results suggest that reduced neuritic activity in the h(alpha)-synuclein-expressing cells might be due, in part, to alterations in cell adhesion capacity. This might be attributed to alpha-synuclein affecting a signal transduction pathway distinct from protein kinase C and protein kinase A.

Animals↗
PubMed2001

Presenilin binding protein is associated with neurofibrillary alterations in Alzheimer's disease and stimulates tau phosphorylation.

A novel presenilin binding protein, PBP, has recently been identified. PBP is localized to the particulate fraction of extracts of Alzheimer's disease brain but is found in the soluble fractions of brain from age matched normal controls. It is shown here that PBP is associated with neurofibrillary tangles in Alzheimer's disease brain. In addition, the expression of PBP increases the phosphorylation of tau in cultured cells. Therefore PBP may have a regulatory role in tau phosphorylation and in the genesis of neurofibrillary tangles.

Aged↗