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Biomedical subjects

M Mallory

Publications and source records attributed to M Mallory.

At least 37 records · Page 2Linked to original sources
PubMed2000

Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice.

Recent studies have shown that amyloid precursor protein (APP), which plays a central role in Alzheimer's disease (AD), protects against excitotoxic neuronal injuries by regulating the function of the glial glutamate transporters. The mechanisms underlying these effects and their relationship to the neurodegenerative process in AD are under intense scrutiny. In this context, the main objective of the present study was to determine if overexpression of mutant human APP in transgenic mouse brains results in altered functioning of the excitatory amino acid transporters (EAATs). Transgenic mice expressing the 695 amino acid form of the human APP from the Thy-1 promoter showed a significant decrease in B(max) and K(D) for aspartate uptake when compared to nontransgenic controls. This decrease in glutamate transporter activity was associated with decreased protein expression of glial specific glutamate transporters, EAAT1 and 2, but did not affect mRNA levels. These results suggest that expression of mutant forms of APP disturbs astroglial transport of excitatory amino acids at the posttranscriptional level leading, in turn, to increased susceptibility to glutamate toxicity.

ATP-Binding Cassette Transporters↗
PubMed2000

Neurotrophic effects of Cerebrolysin in animal models of excitotoxicity.

Excitotoxicity might play an important role in neurodegenerative disorders such as Alzheimer's disease. In the mouse brain, kainic acid (KA) lesioning results in neurodegeneration patterns similar to those found in human disease. For this study, two sets of experiments were performed in order to determine if Cerebrolysin ameliorates the alterations associated with KA administration. In the first set of experiments, mice received intraperitoneal KA injections followed by Cerebrolysin administration, while in the second, mice were pretreated with Cerebrolysin for 4 weeks and then challenged with KA. Behavioral testing in the water maze and assessment of neuronal structure by laser scanning confocal microscopy showed a significant protection against KA lesions in mice pretreated with Cerebrolysin. In contrast, mice that received Cerebrolysin after KA injections did not show significant improvement. This study supports the contention that Cerebrolysin might have a neuroprotective effect in vivo against excitotoxicity.

Amino Acids↗
PubMed2000

C-terminal alpha-synuclein immunoreactivity in structures other than Lewy bodies in neurodegenerative disorders.

alpha-Synuclein is a presynaptic terminal protein that accumulates abnormally in plaques in Alzheimer's disease (AD), in Lewy bodies in Lewy body disease (LBD) and in filamentous inclusions in multiple system atrophy. Since it has been previously shown that proteinase K or formic acid pretreatment enhances alpha-synuclein immunoreactivity in Lewy bodies and plaques, we hypothesized that the immunoreactivity in tangles, glial cells and Pick bodies might be revealed by such pretreatment. Brain sections from patients with AD, LBD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease were pretreated with proteinase K or formic acid and immunostained with antibodies against the N-terminal, C-terminal or non-amyloid beta component of AD amyloid (NAC) regions of alpha-synuclein. This study showed that after proteinase K (but not formic acid) pretreatment the anti-C terminus antibody immunostained neurofibrillary tangles of AD, PSP and CBD, and glial inclusions of PSP and CBD, as well as Pick bodies. Western blot analysis confirmed that in cases other than LBD, the anti-C terminus antibodies also recognized the native alpha-synuclein band and no cross-reactive bands were observed. In contrast, in LBD, after formic acid pretreatment with the anti-NAC antibody astroglial cells and granular neurons were immunostained. The N-terminal region antibody only recognized the lesions in LBD cases and not those of other neurodegenerative disorders. These results support the view that different fragments of alpha-synuclein might play an important role in the pathogenesis of several neurodegenerative disorders.

Aged↗
PubMed2000

alpha-synuclein promotes mitochondrial deficit and oxidative stress.

Abnormal accumulation of the presynaptic protein alpha-synuclein has recently been implicated in the pathogenesis of Alzheimer's and Parkinson's diseases. Because neurodegeneration in these conditions might be associated with mitochondrial dysfunction and oxidative stress, the effects of alpha-synuclein were investigated in a hypothalamic neuronal cell line (GT1-7). alpha-Synuclein overexpression in these cells resulted in formation of alpha-synuclein-immunopositive inclusion-like structures and mitochondrial alterations accompanied by increased levels of free radicals and decreased secretion of gonadotropin-releasing hormone. These alterations were ameliorated by pretreatment with anti-oxidants such as vitamin E. Taken together these results suggest that abnormal accumulation of alpha-synuclein could lead to mitochondrial alterations that may result in oxidative stress and, eventually, cell death.

Animals↗
PubMed2000

Deletions of structural glycoprotein E2 of classical swine fever virus strain alfort/187 resolve a linear epitope of monoclonal antibody WH303 and the minimal N-terminal domain essential for binding immunoglobulin G antibodies of a pig hyperimmune serum.

The major structural glycoprotein E2 of classical swine fever virus (CSFV) is responsible for eliciting neutralizing antibodies and conferring protective immunity. The current structural model of this protein predicts its surface-exposed region at the N terminus with a short stretch of the C-terminal residues spanning the membrane envelope. In this study, the N-terminal region of 221 amino acids (aa) covering aa 690 to 910 of the CSFV strain Alfort/187 E2, expressed as a fusion product in Escherichia coli, was shown to contain the epitope recognized by a monoclonal antibody (WH303) with affinity for various CSFV strains but not for the other members of the Pestivirus genus, bovine viral diarrhea virus (BVDV) and border disease virus (BDV). This region also contains the sites recognized by polyclonal immunoglobulin G (IgG) antibodies of a pig hyperimmune serum. Serial deletions of this region precisely defined the epitope recognized by WH303 to be TAVSPTTLR (aa 829 to 837) of E2. Comparison of the sequences around the WH303-binding site among the E2 proteins of pestiviruses indicated that the sequence TAVSPTTLR is strongly conserved in CSFV strains but highly divergent among BVDV and BDV strains. These results provided a structural basis for the reactivity patterns of WH303 and also useful information for the design of a peptide containing this epitope for potential use in the detection and identification of CSFV. By deletion analysis, an antigenic domain capable of reacting with pig polyclonal IgG was found 17 aa from the WH303 epitope within the N-terminal 123 residues (aa 690 to 812). Small N- or C-terminal deletions introduced into the domain disrupt its reactivity with pig polyclonal IgG, suggesting that this is the minimal antigenic domain required for binding to pig antibodies. This domain could have eliminated or reduced the cross-reactivity with other pestiviruses and may thus have an application for the serological detection of CSFV infection; evaluation of this is now possible, since the domain has been expressed in E. coli in large amounts and purified to homogeneity by chromatographic methods.

Adenovirus E2 Proteins↗
PubMed2000

Synaptic pathology in Borna disease virus persistent infection.

Borna disease virus (BDV) infection of newborn rats leads to a persistent infection of the brain, which is associated with behavioral and neuroanatonomical abnormalities. These disorders occur in the absence of lymphoid cell infiltrates, and BDV-induced cell damage is restricted to defined brain areas. To investigate if damage to synaptic structures anteceded neuronal loss in BDV neonatally infected rats, we analyzed at different times postinfection the expression levels of growth-associated protein 43 and synaptophysin, two molecules involved in neuroplasticity processes. We found that BDV induced a progressive and marked decrease in the expression of these synaptic markers, which was followed by a significant loss of cortical neurons. Our findings suggest that BDV persistent infection interferes with neuroplasticity processes in specific cell populations. This, in turn, could affect the proper supply of growth factors and other molecules required for survival of selective neuronal populations within the cortex and limbic system structures.

Animals↗
PubMed2000

Vitamin E supplementation prevents spatial learning deficits and dendritic alterations in aged apolipoprotein E-deficient mice.

Recent studies have suggested that altered function of apolipoprotein E might lead to Alzheimer's disease via oxidative stress. In this context, the objective of this study was to determine if antioxidative treatment with vitamin E was neuroprotective in apolipoprotein E-deficient mice. For this purpose, 1-month-old control and apolipoprotein E-deficient mice received dietary vitamin E for 12 months. We showed that, compared to apolipoprotein E-deficient mice who received a regular diet, mice treated with vitamin E displayed a significantly improved behavioural performance in the Morris water maze. This improved performance was associated with preservation of the dendritic structure in vitamin E-treated apolipoprotein E-deficient mice. In addition, whilst untreated apolipoprotein E-deficient mice displayed increased levels of lipid peroxidation and glutathione, vitamin E-treated mice showed near normal levels of both lipid peroxidation and glutathione. These results support the contention that vitamin E prevents the age-related neurodegenerative alterations in apolipoprotein E-deficient mice.

Animals↗
PubMed1999

Alternative splicing patterns of CYP2D genes in human brain and neurodegenerative disorders.

The expression patterns of alternatively spliced forms of the CYP2D (6, 7, 7A, 7B) gene were analyzed in the brains of individuals with Lewy body disease (LBD) and correlated with CYP2D6 polymorphisms. Five different alternatively spliced transcripts were identified. The most common was the deletion of exon 6 (87.3% of cases), followed by a 91-base pair fragment deletion at the 3' end of the gene (63.9% of cases). There was no correlation between the polymorphisms in the CYP2D6B gene or presence of LBD and these five alternatively spliced transcripts. Susceptibility to LBD may occur through mechanisms other than altered mRNA splicing of the CYP2D6 gene.

Aged↗
PubMed1999

Differential neurotrophic effects of apolipoprotein E in aged transgenic mice.

The present study seeked to determine whether the neurodegenerative and cognitive alterations in aged apolipoprotein E-deficient mice are differentially reversed by transgenic overexpression of human apolipoprotein-E3 vs. apolipoprotein-E4 in the background of deficient endogenous apolipoprotein E. These studies showed dendritic alterations in pyramidal neurons of apolipoprotein-E4 transgenic mice, similar to the ones observed in apolipoprotein E-deficient mice. However, these mice had a preserved density of synaptophysin-immunoreactive presynaptic terminals. In contrast, mice overexpressing apolipoprotein-E3 showed no synapto-dendritic alterations. Analysis of behavioral performance in the Morris water maze showed that while apolipoprotein E-deficient mice performed poorly, overexpression of apolipoprotein-E3 and, to a lower extent apolipoprotein-E4, resulted in an improved performance. This study supports the contention that, compared with apolipoprotein-E4, apolipoprotein-E3 might have a greater neurotrophic in vivo effect in aged mice.

Aging↗
PubMed1999

Aberrant presenilin-1 expression downregulates LDL receptor-related protein (LRP): is LRP central to Alzheimer's disease pathogenesis?

Low density lipoprotein receptor-related protein (LRP) polymorphisms have recently been associated with an increased susceptibility of Alzheimer's disease (AD). Furthermore, LRP has been linked to molecules that confer susceptibility to AD (apolipoprotein E, alpha-2-macroglobulin, amyloid precursor protein), previously with the exception of the presenilins. Here we report that aberrant presenilin-1 expression in vivo and in vitro downregulates LRP. Specifically, transgenic mice overexpressing the M146L or L286V presenilin-1 mutation show decreased levels of LRP expression in neuronal populations where presenilin-1 and LRP are closely colocalized or coexpressed. Moreover, cell lines transfected with presenilin-1 also expressed decreased levels of LRP. These findings suggest that LRP may be central to AD pathogenesis since all proteins genetically associated with AD can now be linked via a single pathway to LRP.

Alzheimer Disease↗
PubMed1999

In vitro synaptotrophic effects of Cerebrolysin in NT2N cells.

Recent studies have shown that Cerebrolysin can enhance synaptic function and ameliorate synaptodendritic alterations in animal models of neurodegeneration, suggesting a synaptotrophic effect. We hypothesize that Cerebrolysin might exert this effect, in part, by regulating the expression of amyloid precursor protein (APP). We studied the patterns of expression of synaptic proteins during differentiation of human teratocarcinoma cell line NTera 2 (NT2) in the presence or absence of Cerebrolysin. This study showed that the terminally differentiated neurons (NT2N) expressed a wide variety of synaptic markers and that expression of these synaptic-associated proteins coincided with the shift in expression from APP770/751 to APP695. Furthermore, APP immunoreactivity was colocalized with synaptophysin-immunoreactive neuritic varicosities in NT2N neurites, and Cerebrolysin treatment of NT2N cells resulted in an augmented and earlier expression of synaptic-associated proteins. This increased synaptic protein expression coincided with an increase in APP695 over APP770/751. These results support the possibility that synaptotrophic effects of Cerebrolysin might be mediated via regulation of APP expression.

Amino Acids↗
PubMed1999

A role for apoE in regulating the levels of alpha-1-antichymotrypsin in the aging mouse brain and in Alzheimer's disease.

This study was designed to explore the possible functional relationships between apolipoprotein E (apoE) and the protease inhibitor alpha-1-antichymotrypsin in the aging mouse brain and in Alzheimer's disease. For this purpose, levels of EB22/5 (the mouse homologue to human alpha-1-antichymotrypsin) mRNA expression was studied in apoE-deficient mice. These mice showed an age-dependent increase of EB22/5 mRNA expression in the brain. Furthermore, overexpression of allele 3 of human APOE gene in transgenic mice (in an apoE-deficient background) resulted in normalization of levels of EB22/5 mRNA expression compatible with levels found in control mice. In contrast, overexpression of human APOE4 allele or down-regulation of the apoE receptor low density lipoprotein receptor-related protein by deletion of the receptor-associated protein was associated with elevated levels of EB22/5 similar to apoE-deficient mice. Consistent with the findings in murine models, human alpha-1-antichymotrypsin protein was increased in brain homogenates from patients with Alzheimer's disease, and levels of this serpin were the highest in patients with the APOE4 allele. In summary, the present study showed evidence supporting a role for apoE in regulating alpha-1-antichymotrypsin expression. This is relevant to Alzheimer's disease because these two molecules appear to be closely associated with the pathogenesis of this disorder.

Aging↗
PubMed1999

Cerebrolysin ameliorates performance deficits, and neuronal damage in apolipoprotein E-deficient mice.

Recent studies suggest that Cerebrolysin improves behavioral performance by affecting synaptic transmission in the hippocampus. The main objective of this study was to determine if Cerebrolysin administration ameliorates the neurodegenerative and performance deficits in aged apolipoprotein E (apoE)-deficient mice. ApoE-deficient mice treated with Cerebrolysin showed a significant improved performance in the Morris water maze, compared to saline-treated apoE-deficient mice. Although the improved performance in the Cerebrolysin-treated apoE-deficient mice was associated with restoration of the neuronal structure, the poor learning ability of saline-treated apoE-deficient mice was related to the a disrupted synaptodendritic structure. This study supports the contention that Cerebrolysin might have a neurotrophic effect in vivo.

Amino Acids↗
PubMed1999

A novel role for receptor-associated protein in somatostatin modulation: implications for Alzheimer's disease.

Receptor-associated protein appears to play an important role in low-density lipoprotein receptor-related protein trafficking. Since ligands for the low-density lipoprotein receptor-related protein have been implicated in Alzheimer's disease and normal functioning of this protein is indispensable for central nervous system development, deficient receptor-associated protein expression may result in central nervous system alterations. In this study, receptor-associated protein knockout mice were behaviorally tested and nervous system integrity was assessed via in situ hybridization and immunocytochemical/laser confocal microscopy methods. Receptor-associated protein knockout mice were found to be cognitively impaired in the Morris water maze compared to controls. In wild-type mice, the receptor-associated protein was found to be highly co-expressed with somatostatin in hippocampal and neocortical inhibitory neurons. Receptor-associated protein knockout mice, however, showed a significant decrease in number of somatostatin-expressing neurons of the CA1 region and somatostatin expression within these neurons. The decreased number of somatostatin neurons significantly correlated with cognitive impairment observed in the receptor-associated protein knockout mice. These results suggest a novel role for receptor-associated protein in modulating the functioning of somatostatin-producing neurons. Furthermore, this has implications for Alzheimer's disease pathogenesis, in which altered regulation of both somatostatin and the known low-density lipoprotein receptor-related protein ligands are a consistent finding.

Alzheimer Disease↗
PubMed1999

Cortical synaptic density is reduced in mild to moderate human immunodeficiency virus neurocognitive disorder. HNRC Group. HIV Neurobehavioral Research Center.

Dendritic and synaptic damage (without frank neuronal loss) may be seen in milder human immunodeficiency virus (HIV)-related cognitive disorders. Synapse volume estimates, performed by stereological methods, could enhance the ability to detect subtle neuronal changes that may accompany cognitive impairment in HIV infection. For the present study, synaptic density and neuronal number were assessed by combined stereology/confocal microscopy and these measures were then correlated with ante-mortem levels of cognitive performance in AIDS patients. Three-dimensional stereological measures showed a significant correlation between reduced synaptic density and poor neuropsychological performance. To evaluate the specificity of any observed associations, additional variables including viral burden, astrogliosis and number of calbindin-immunoreactive neurons were measured. Factor analysis of a set of neuropathological variables revealed two factors; one defined by synaptic density and volume fraction, calbindin pyramidal neuronal densities and viral burden; the second by astrocytosis and calbindin interneuron density. Only the first factor correlated significantly with neuropsychological functioning during life. It is concluded that a combination of factors including synaptic damage, specific neuronal loss and increasing viral load underlies HIV-associated cognitive impairment. As synaptic damage is potentially reversible, early diagnosis and treatment of mild cogntive disorders may improve functioning and prevent the progression of brain disease.

AIDS Dementia Complex↗
PubMed1998

Increased levels of alpha-1-antichymotrypsin in brains of patients with Alzheimer's disease correlate with activated astrocytes and are affected by APOE 4 genotype.

Levels of alpha-1-antichymotrypsin (ACT) were higher in brain homogenates of patients with Alzheimer's disease (AD) than controls. Brain tissues from the same patients and controls were immunostained with antibodies specific for microglia or astrocytes, the leukocyte common antigen (CD45) and glial fibrillary acidic protein (GFAP), respectively. Both activated CD45 and GFAP cells were increased in AD. Astroglia were divided into scattered (CD45sc) and clustered microglia (CD45cl) or scattered (GFAPsc) and clustered astrocytes (GFAPcl). Clustered cells were defined according their tendency to form focal aggregates. CD45cl and GFAPcl cells were present only in AD brain, while CD45sc and GFAPsc positive cells were present either in AD or control brains, with AD brains showing increased numbers of both cell types. A positive correlation between brain ACT levels and the number of GFAPsc positive cells was present in AD. AD patients with APOE 4 allele showed increased levels of ACT and increased CD45sc positive cells. Elevated ACT levels in the brain of AD patients could be interpreted as a metabolic response of astrocytes which might modulate the potentially deleterious activation of microglia cells.

Aged↗
PubMed1998

Amyloid protein precursor stimulates excitatory amino acid transport. Implications for roles in neuroprotection and pathogenesis.

Excitatory neurotransmitters such as glutamate are required for the normal functioning of the central nervous system but can trigger excitotoxic neuronal injury if allowed to accumulate to abnormally high levels. Their extracellular levels are controlled primarily by transmitter uptake into astrocytes. Here, we demonstrate that the amyloid protein precursor may participate in the regulation of this important process. The amyloid protein precursor has been well conserved through evolution, and a number of studies indicate that it may function as an endogenous excitoprotectant. However, the mechanisms underlying this neuroprotective capacity remain largely unknown. At moderate levels of expression, human amyloid protein precursors increased glutamate/aspartate uptake in brains of transgenic mice, with the 751-amino acid isoform showing greater potency than the 695-amino acid isoform. Cerebral glutamate/aspartate transporter protein levels were higher in transgenic mice than in non-transgenic controls, whereas transporter mRNA levels were unchanged. Amyloid protein precursor-dependent stimulation of aspartate uptake by cultured primary astrocytes was associated with increases in protein kinase A and C activity and could be blocked by inhibitors of these kinases. The stimulation of astroglial excitatory amino acid transport by amyloid protein precursors could protect the brain against excitotoxicity and may play an important role in neurotransmission.

Amyloid beta-Protein Precursor↗