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Biomedical subjects

E Masliah

Publications and source records attributed to E Masliah.

At least 163 records · Page 9Linked to original sources
PubMed1996

Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism.

There are two distinct viewpoints on the association of the inheritance of apolipoprotein E (APOE) alleles and the age of onset distribution of Alzheimer's disease (AD): genetic and phenotypic expression. There have been multiple corroborations of the APOE-epsilon 4 association with Alzheimer's disease in populations around the world in clinic based studies as well as emerging epidemiological studies. The genetic data do not imply mechanism of pathogenesis. The phenotypic expression of AD has been based in theories based on amyloid plaques or neurofibrillary tangles. ApoE protein interacts with both beta-amyloid and tau in an isoform-specific manner. The interaction with tau had been thought to be an in vitro artifact, since apoE had not been previously localized to the neuronal cytoplasm. Immuno-EM studies have localized apoE in neuronal cytoplasm. ApoE3 interacts with both tau and MAP2c at the microtubule binding repeat domain under conditions in which apoE4 is less tightly bound. These data further support a hypothesis that apoE3 (and apoE2) protect the microtubule binding domain of tau from binding to itself to form paired helical filaments and neurofibrillary tangles, while protecting the site for microtubule stabilizing interactions with beta-tubulin. These data are supported by recent data from APOE knock-out mice demonstrating dendritic alterations leading to synaptic simplification similar to that observed in AD.

Age of Onset↗
PubMed1996

Prevention of HIV-1 gp120-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine.

To investigate the in vivo role of NMDA receptor stimulation in HIV-1-related CNS neurotoxicity, we evaluated the neuroprotective potential of the NMDA receptor antagonist memantine in transgenic mice which have gp120-induced CNS damage. Brains of mice treated chronically with memantine and of untreated controls were analysed for structural damage by laser scanning confocal microscopy of sections immunolabeled for microtubule-associated protein-2 (MAP-2) and synaptophysin. Qualitative and quantitative analysis of confocal images revealed that memantine treatment substantially decreased neuropathology in gp120 transgenic mice; this included statistically significant improvements in both dendritic and presynaptic terminal density. These results provide in vivo evidence that gp120 can activate neurotoxic pathways that can ultimately result in aberrant NMDA receptor stimulation and neuronal damage in the CNS. They also suggest that clinically tolerated NMDA receptor antagonists may be useful in the prevention of neuronal damage in HIV-1-infected patients.

Animals↗
PubMed1996

Genetic studies in Alzheimer's disease with an NACP/alpha-synuclein polymorphism.

The non-Abeta component of Alzheimer's disease amyloid (NAC) is copurified with amyloid from the brain tissue of Alzheimer's disease victims and is immunohistochemically localized to amyloid fibrils. NAC is a hydrophobic peptide fragment from the NAC precursor protein (NACP/alpha-synuclein) that is localized to presynaptic terminals. We used a polymorphic dinucleotide repeat sequence in a genomic clone of NACP for genetic association and linkage studies. Screening of Alzheimer's disease families failed to establish linkage between NACP and Alzheimer's disease. Nevertheless, one of the NACP polymorphisms (NACP allele 2) was shown to have significant association with healthy elderly control individuals with apolipoprotein E risk. This may indicate a possible protective function of the allele.

Aged↗
PubMed1996

Deficient glutamate transport is associated with neurodegeneration in Alzheimer's disease.

The mechanisms of synapse damage in Alzheimer's disease (AD) are not fully understood. Deficient functioning of glutamate transporters might be involved in synaptic pathology and neurodegeneration by failing to clear excess glutamate at the synaptic cleft. In AD, glutamate transporter activity as assessed by D-[3H]aspartate binding is decreased; however, it is not clear to what extent it is associated with the neurodegenerative process and cognitive alterations. For this purpose, levels of D- and L-[3H]aspartate binding in midfrontal cortex were correlated with synaptophysin levels, brain spectrin degradation product levels, and clinical and neuropathological indicators of AD. Compared to control brains, AD brains displayed a 34% decrease in levels of D-[3H]aspartate binding, a 30% decrease in L-[3H]aspartate binding, and a 48% loss of synaptophysin immunoreactivity. Increased levels of brain spectrin degradation products correlated with a decrease in levels of D-[3H] and L-[3H]aspartate binding, and decreased levels of synaptophysin immunoreactivity. Levels of L-[3H]aspartate binding correlated with levels of synaptophysin immunoreactivity. These results suggest that decreased glutamate transporter activity in AD is associated with increased excitotoxicity and neurodegeneration, supporting the possibility that abnormal functioning of this system might be involved in the pathogenesis of synaptic damage in AD.

ATP-Binding Cassette Transporters↗
PubMed1996

Neuropsychological deficits associated with diffuse Lewy body disease.

Diffuse Lewy body disease (DLBD), in its pure form, is a neuropathologic condition in demented patients that is characterized by subcortical and diffusely distributed neocortical Lewy bodies with little or no concomitant Alzheimer's disease (AD) pathology. Clinically, DLBD patients initially present with dementia of insidious onset and subsequently develop mild extrapyramidal motor dysfunction. The present study retrospectively examined the neuropsychological test performance of five patients with DLBD and compared their performance to that of equally demented patients with neuropathologically confirmed "pure" AD. The results showed that the DLBD patients were globally demented with deficits in memory, attention, language, psychomotor performance, and "executive" functions, and a strikingly severe deficit in visuospatial and visuoconstructive abilities. The visuoconstructive and psychomotor impairments of the DLBD patients were significantly worse than those of the AD patients, whereas the memory performance of the AD patients was worse than that of the DLBD patients. These results indicate that DLBD without concomitant AD pathology can produce a global dementia with aspects of both cortical and subcortical dysfunction and suggests that Lewy body pathology contributes importantly to the clinical manifestation of the Lewy body variant of AD.

Aged↗
PubMed1996

Glutamate-dependent long-term presynaptic changes in corticostriatal excitability.

We have previously shown that brief high frequency stimulation of the anteromedial prefrontal cortex induces a long-term decrease in excitability of the glutamatergic corticostriatal terminal field. In contrast, a long-term increase in presynaptic corticostriatal excitability may be induced by presenting two brief cortical tetanizing stimuli separated by 2-3 min such that the second tetanus coincides with a period of increased excitability elicited by the first. In the present study, we examined the glutamate receptor subtypes involved in these long-term changes in presynaptic excitability. A specific glutamate receptor antagonist was infused into the rat striatum 10-25 min prior to either a single or double cortical tetanic stimulation. To eliminate the participation of intrinsic striatal cells, a subset of animals received a striatal kainic acid lesion eight to 20 days before the recording experiment. Antagonists of the N-methyl-D-aspartate and metabotropic glutamate receptor subtypes were effective in blocking the decrease in excitability induced by single cortical tetanic stimulation whereas an antagonist of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptor did not prevent the induction of a long-term reduction in excitability. In contrast, each of these antagonists prevented the induction of a long-term increase in excitability. These long-term modifications in excitability of the presynaptic glutamate axon terminals appear to be induced by similar mechanisms to those postulated to operate in long-term potentiation and depression. These enduring changes in presynaptic excitability are likely to represent important mechanisms for the selective modification of information processing in the striatum.

Action Potentials↗
PubMed1996

Alterations in apolipoprotein E expression during aging and neurodegeneration.

Apolipoprotein E (apoE) is a 34 kDa protein that plays an important role in cholesterol transport, uptake and redistribution. Within the nervous system, apoE might be involved in maintaining synaptic integrity after injury and during aging. ApoE might help maintain the integrity of the synaptodendritic complex by several different mechanisms. Among them, recent studies have suggested that apoE: (1) stabilizes the neuronal cytoskeleton; (2) plays an important role in transporting esterified cholesterol to neurons undergoing reinnervation where it is taken up by the low density lipoprotein receptor-related protein pathway and used as a precursor for the synthesis of new synaptic terminals; (3) regulates interactions between neurons and the extracellular matrix (e.g. laminin); and (4) regulates levels of intracellular calcium. The main objective of the manuscript is to review the current progress in understanding the functions of apoE in the nervous system and how malfunctioning of this molecule might result in neurodegenerative disorders such as Alzheimer's disease.

Aging↗
PubMed1996

Neocortical lewy body counts correlate with dementia in the Lewy body variant of Alzheimer's disease.

Patients with the Lewy body variant (LBV) of Alzheimer's disease (AD) meet diagnostic criteria for AD but have a lighter burden of plaque and tangle AD pathology despite comparable dementia. We quantified neocortical Lewy bodies (LB) in LBV patients (n = 14) using anti-ubiquitin polyclonal antibody, selecting for quantification those neocortical regions with the highest densities of LB. Neocortical neurofibrillary tangles (NFT) and neuritic plaques were evaluated with thioflavin- S. A group of classical AD patients (n = 12), matched for disease duration, was also studied. For most of these cases, entorhinal neurofibrillary pathology had previously been assessed by applying a modification of the Braak and Braak AD staging protocol. Although LBV and AD groups had similar mental test scores when last evaluated prior to death, lower neocortical NFT and plaque counts and lower modified Braak stages were observed in LBV. Neocortical NFT counts correlated with impaired neuropsychological test performance in AD but not in LBV. Plaque counts did not correlate with mental status in either group. Lewy body concentrations in four neocortical areas correlated significantly with dementia severity in LBV. The association of AD lesions in the neocortex with dementia in LBV was comparatively weaker than that observed for LB concentrations. These findings suggest that neocortical LB combined with entorhinal NFT or subcortical Parkinson's disease-type pathology may equalize the degree of dementia seen in LBV with that encountered in classical AD.

Aged↗
PubMed1996

Macrophage Activation Factors in the Brains of AIDS Patients.

HIV, soluble HLA class I (sHLA-I), quinolinic acid (QUIN), and the monokines IL-1β, IL-6, and TNF-α were measured by ELISA and PCR in brain tissue of 60 AIDS autopsies without evidence of CNS opportunistic infections. Individual cases showed good interrogational correlations for the factors measured. There was a positive correlation between concentrations of IL-1β and IL-6. Brain viral burden correlated with intraparenchymal levels of sHLA-I, IL-1β, and IL-6. Comparison of neuritic damage and levels of immune mediators implicates macrophage activation factors in the etiology of neurologic damage in AIDS.

AIDS Dementia Complex↗
PubMed1996

Pathogenesis of HIV-1 associated neurodegeneration.

A significant number of people infected with the human immunodeficiency virus (HIV) develop neurologic complications. The AIDS dementia complex is frequently accompanied by HIV encephalitis, which is characterized at the neuropathologic level by loss of neuronal subpopulations in the neocortex, limbic system, and basal ganglia in association with synaptic and dendritic damage, astrogliosis, and formation of microglial nodules and multinucleated giant cells. Recent studies have shown that the extent of neurodegeneration in this condition correlates directly with the amount of HIV-1 antigen in the brain. HIV-1 infection of the brain could result in neurodegeneration via neurotoxic effects of viral products (e.g., gp 120, Nef, Tat) and/or via alterations in the expression of host factors. The latter may include increased production of potentially detrimental factors such as cytokines, excitotoxic amino acids, free oxygen radicals, and bioactive lipid mediators as well as interference with the production or action of neurotrophic/protective factors. Derangements of the neuronal calcium homeostasis, lipid peroxidation, and induction of programmed cell death (apoptosis) may all play a role as final common pathogenetic pathways in HIV-1-induced neurodegeneration. Recent studies in transgenic mice (over)expressing HIV- or host-derived proteins in their central nervous system indicate that distinct neuronal populations may differ in their susceptibility to specific pathogenic factors. For example, glutamate-receptor-bearing pyramidal neurons were particularly susceptible to neurodegeneration promoted by HIV-1 products, whereas interneurons were more sensitive to the neurotoxic effects mediated by cytokines. For the design of effective treatments for the HIV-1-associated cognitive/motor complex, it will be important to determine whether the neurologic deficits in this entity result from global neuronal dysfunction or relate more specifically to the impairment of distinct neuronal subpopulations. It will also be critical to examine diverse in vitro and in vivo models to help decide which of the many pathogenetic processes that may be at work in this complex disease constitute the most promising therapeutic targets.

AIDS Dementia Complex↗
PubMed1996

Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer's disease.

We have recently identified, in the brain tissue of patients afflicted with Alzheimer's disease (AD), the non-A beta component of AD amyloid (NAC) as a new constituent of amyloid. NAC is derived from a larger precursor, NACP, a presynaptic protein. To better understand the role of NACP/NAC in the pathogenesis of AD, we used semiquantitative immunoblotting and combined double-immunocytochemistry/laser scanning confocal microscopy to study the concentration and distribution of NACP/NAC in human brain, and compared them to the concentration and distribution of the presynaptic marker synaptophysin and the amyloid marker A beta. The semiquantitative immunoblotting demonstrated that the NACP concentration is slightly increased in the AD frontal cortex without statistical significance, whereas synaptophysin was reduced in its levels in AD. Consequently the proportion of NACP/synaptophysin was more than double in the AD frontal cortex as compared with controls. In the AD neocortex, NACP was colocalized with approximately 80% of the synaptophysin-immunoreactive structures (presumably the presynaptic terminals) and with the dystrophic neuritic component of the plaques. Computer-aided analysis showed that numbers of NACP-immunoreactive structures along synaptophysin-immunoreactive structures were significantly diminished (30 to 40%) in AD. Although the overall numbers of NACP-positive structures were decreased, there was a significant increase in the intensity of NACP-immunoreactivity per structure in AD. This increased intensity of NACP immunoreactivity per structure in AD was not observed with anti-synaptophysin, consistent with immunoblotting-based quantification. Antibodies against NAC immunoreacted with amyloid in 35% of the diffuse plaques and 55% of the mature plaques. Normal aged control brains containing small groups of diffuse plaques were negative with anti-NAC. Double-immunolabeling studies with A beta antibodies showed that NAC immunoreactivity is more abundant in the center portion of amyloid rather than in the periphery. These studies suggest that there is a connection between metabolism of presynaptic proteins and amyloid formation, and that NAC might follow diffuse A beta accumulation resulting in the formation of compact amyloid and mature plaques.

Aged↗
PubMed1995

Levels and alternative splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer's disease.

Abnormal expression of human amyloid precursor protein (hAPP) gene products may play a critical role in Alzheimer's disease (AD). Recently, a transgenic model was established in which platelet-derived growth factor (PDGF) promoter-driven neuronal expression of an alternatively spliced hAPP minigene resulted in prominent AD-type neuropathology (Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., Guido, T., Hagopian, S., Johnson-Wood, K., Khan, K., Lee, M., Leibowitz, P., Lieberburg, I., Little, S., Masliah, E., McConlogue, L., Montoya-Zavala, M., Mucke, L., Paganini, L., and Penniman, E. (1995) Nature 373, 523-527). Here we compared the levels and alternative splicing of APP transcripts in brain tissue of hAPP transgenic and nontransgenic mice and of humans with and without AD. PDGF-hAPP mice showed severalfold higher levels of total APP mRNA than did nontransgenic mice or humans, whereas their endogenous mouse APP mRNA levels were decreased. This resulted in a high ratio of mRNAs encoding mutated hAPP versus wild-type mouse APP. Modifications of hAPP introns 6, 7, and 8 in the PDGF-hAPP construct resulted in a prominent change in alternative splice site selection with transcripts encoding hAPP770 or hAPP751 being expressed at substantially higher levels than hAPP695 mRNA. Frontal cortex of humans with AD showed a subtle increase in the relative abundance of hAPP751 mRNA compared with normal controls. These data identify specific intron sequences that may contribute to the normal neuronspecific alternative splicing of APP pre-mRNA in vivo and support a causal role of hAPP gene products in the development of AD-type brain alterations.

Aged↗
PubMed1995

NGF-mediated synaptic sprouting in the cerebral cortex of lesioned primate brain.

In the present study, coronal brain sections of cortically devascularized non-human primates (Cercopithecus aethiops) were used to assess the lesion-associated synaptic loss, and the effect of exogenous nerve growth factor (NGF) in preventing or reversing this neurodegeneration. The sections were immunolabeled with antibodies against the synaptic marker protein synaptophysin (SYN), as well as choline acetyltransferase (ChAT) and parvalbumin (PV) markers that identify cholinergic neurons and interneurons, respectively. We found that, compared to sham-operated animals, in the lesioned vehicle treated animals SYN immunoreactivity near the lesioned site in the frontoparietal cortex was decreased by 31%. Similarly, corrected optical density values of immunostained sections specific for ChAT in the nucleus basalis of Meynert (ipsilateral to the lesion) decreased by 20% and PV-immunoreactive neurons near the lesion decreased by 47%. In contrast, NGF-treated lesioned animals showed levels of SYN, ChAT, and PV immunoreactivity similar to sham controls. These results are consistent with previous studies and support the view that NGF may not only prevent neurodegenerative changes after neocortical infarction by protecting vulnerable neurons, but also is capable of inducing sprouting and synaptogenesis.

Animals↗
PubMed1995

Non-A beta component of Alzheimer's disease amyloid (NAC) is amyloidogenic.

The non-A beta component of Alzheimer's disease (AD) amyloid (NAC) was identified biochemically as the second major component in the amyloid purified from brain tissue of AD patients. NAC, derived from its 140 amino acid long precursor, NACP, is at least 35 amino acids long (NAC35) although its amino terminus is not definitely determined. An antiserum, anti-NAC-X1, was raised against the amino-terminal 9 amino acid sequence of NAC35 and purified on a peptide affinity column. This affinity-purified anti-NAC-X1 antibody immunostained amyloid in AD brain sections and recognized NAC35 but not NACP on Western or dot blot. In aqueous solutions, synthetic NAC35 self-aggregated in a time-, concentration-, and temperature-dependent manner. NAC35 was detected initially as a monomer with a molecular mass of 3500 Da but became aggregated as a function of time into a higher molecular mass component that could not migrate into the gel. The aggregate of NAC35 showed green-gold birefringence after Congo red staining when analyzed under polarized light and fiber-like structure when analyzed ultrastructurally. These results suggest that NAC can form amyloid after it has been cleaved out of its precursor and may be a crucial factor in amyloidosis in the AD brain.

Alzheimer Disease↗
PubMed1995

Protection against HIV-1 gp120-induced brain damage by neuronal expression of human amyloid precursor protein.

Expression of the HIV-1 envelope protein gp120 in brains of transgenic (tg) mice induces extensive neurodegeneration (Toggas, S. M., E. Masliah, E. M. Rockenstein, G. F. Rall, C. R. Abraham, and L. Mucke. 1994. Nature [Lond.]. 367:188-193.). To further analyze the pathogenesis of gp120-induced neurotoxicity and to assess the neuroprotective potential of human amyloid precursor proteins (hAPPs) in vivo, different hAPP isoforms were expressed in neurons of gp120/hAPP-bigenic mice: hAPP751, which contains a Kunitz-type protease inhibitor domain, or hAPP695, which lacks this domain. Bigenic mice overexpressing hAPP751 at moderate levels showed significantly less neuronal loss, synapto-dendritic degeneration, and gliosis than singly tg mice expressing gp120 alone. In contrast, higher levels of hAPP695 expression in bigenic mice failed to prevent gp120-induced brain damage. These data indicate that hAPP can exert important neuroprotective functions in vivo and that the efficiency of this protection may depend on the hAPP isoform expressed and/or on the level of neuronal hAPP expression. Hence, molecules that mimic beneficial APP activities may be useful in the prevention/treatment of HIV-1-associated nervous system damage and, perhaps, also of other types of neural injury.

AIDS Dementia Complex↗