Biomedical subjects

M Mallory

Publications and source records attributed to M Mallory.

At least 19 recordsLinked to original sources

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↗

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

Standardization of smooth lipopolysaccharide preparations for use in diagnostic serological tests for bovine antibody Brucella abortus.

A procedure for standardizing Brucella abortus smooth lipopolysaccharide used in diagnostic tests for brucellosis is proposed. The procedure is based on the reactivity of antigen preparations with a panel of sera with or without antibody to B. abortus using a set of parameters established with 13 antigen preparations. For each serum dilution, a mean and two standard deviations were calculated in the indirect and competitive enzyme immunoassays. If data obtained with an antigen preparation, using the same serum dilutions, falls within the range established using two standard deviations, the antigen would be considered acceptable for diagnostic use.

Animals↗

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

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↗

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

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

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

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↗

PubMed1997

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

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

Alzheimer Disease↗

PubMed1997

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

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

Amyloid beta-Protein Precursor↗

PubMed1997

Neurodegeneration of somatostatin-immunoreactive neurons in HIV encephalitis.

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

Basal Ganglia↗

PubMed1997

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

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

ATP-Binding Cassette Transporters↗

PubMed1997

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

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

Aged↗

PubMed1996

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

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

Animals↗

PubMed1996

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

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

Alzheimer Disease↗