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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
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↗
PubMed1996

Viral persistence in neurons alters synaptic plasticity and cognitive functions without destruction of brain cells.

Neurons have a restricted expression of MHC heavy chain molecules which prevents presentation of antigens of infecting viruses. As a result, such infected cells escape immune surveillance and allow the establishment of noncytolytic persistent infection. Here we show that a chronic noncytolytic viral infection both in vitro and in vivo selectively perturbed the expression of GAP-43, a protein that plays a central role in neuronal plasticity processes accompanying learning and memory. GAP-43 expression was greatly decreased in the hippocampus, an area of heightened viral replication, while synaptic density was preserved. Concurrently, the ability to learn tasks was significantly impaired in these persistently infected mice. Yet, infected neurons remained free from structural injury.

Animals↗
PubMed1996

The synaptic protein NACP is abnormally expressed during the progression of Alzheimer's disease.

NACP, the precursor of non-A beta component of Alzheimer's disease (AD) amyloid (NAC), is a synaptic protein that could potentially be involved in AD. We studied, by dot-blot, NACP levels in the frontal cortex of AD cases staged according to severity of disease and correlated them with cognitive performance and neuropathological markers. Early AD cases showed one fold higher levels of NACP immunoreactivity (IR) compared to moderate and severe AD. Levels of NACP-IR were correlated with tangle counts (r = -0.305, P = 0.04) and Blessed score (r = -0.356, P = 0.01), but not with plaque counts (r = 0.132, P = 0.39). This study suggests that the abnormal accumulation of NACP during the early stages of AD might play an important role in the mechanisms of neurodegeneration and synaptic damage in AD.

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

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

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

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↗
PubMed1995

Fragmentation of the neuronal cytoskeleton in the Lewy body variant of Alzheimer's disease.

We studied neuronal alterations in the Lewy body variant of Alzheimer's disease (LBV) with a monoclonal antibody (SMI32) against non-phosphorylated neurofilament proteins, and compared them with the alterations found in pure Alzheimer's disease (AD). A characteristic granular and fragmented appearance of SMI32-immunolabeled pyramidal neurons in layers 3 and 5 of the neocortex occurred in 78% of the LBV cases and was not found in the pure AD cases. Lewy bodies (LBs) in pyramidal neurons in layers 5 and 6 immunoreacted with SMI32 in 44% of the LBV cases. These alterations may be associated with the cognitive deficits found in LBV and are suggestive of an underlying, widespread pathology that includes both disruption of the neurofilamentous cytoskeleton and formation of LBs.

Aged↗
PubMed1995

Neurodegeneration in the central nervous system of apoE-deficient mice.

Apolipoprotein E (apoE) is involved in the development and regeneration of the central nervous system (CNS). ApoE may also be necessary to maintain the integrity of the synapto-dendritic complexity. We analyzed the synaptic alterations in the CNS of apoE-deficient (knockout) mice during the aging process. In apoE-deficient homozygous mice, there was an age-dependent 15 to 40% loss of synaptophysin-immunoreactive nerve terminals and microtubule-associated protein 2-immunoreactive dendrites in the neocortex and hippocampus, when compared to controls. Dendritic alterations were observed as early as 4 months of age. Ultrastructural analysis revealed extensive dendritic vacuolization and disruption of the endomembrane system and cytoskeleton in apoE-deficient homozygous mice. Further immunocytochemical studies of the neuronal cytoskeleton showed that in apoE-deficient mice there was a decrease in the immunoreactivity of alpha and beta tubulin (but not kinesin) in the cell bodies and processes. These results support the contention that apoE might play an important role in maintaining the stability of the synapto-dendritic apparatus and that altered or deficient functioning of this molecule could underlie the synaptic and cytoskeletal alterations in Alzheimer's disease.

Aging↗
PubMed1995

Synaptic loss in cognitively impaired aged rats is ameliorated by chronic human nerve growth factor infusion.

In the present study, we assessed the synaptic changes in aged impaired and unimpaired rats, and the effect of exogenous human nerve growth factor administration on behavioral activity and synaptic density. Human nerve growth factor was administered into the rat ventricles with a cannula connected to an osmotic pump in adult, aged impaired and unimpaired rats. Behavioral performance was evaluated in the Morris water maze. Aged impaired rats had an 18 +/- 4% decrease in the number of synaptophysinimmunoreactive presynaptic terminals as compared to aged unimpaired rats. After a continuous four-week human nerve growth factor, the aged impaired rats displayed a significant 16 +/- 3% increase in the number of synaptophysin-immunoreactive presynaptic terminals in the frontal cortex, as compared to aged impaired rats treated with vehicle. This increase correlated with an improvement in water maze performance (r = -0.74, P < 0.001). Measurements of synaptophysin-immunoreactive presynaptic terminals in other cortical and subcortical regions did not show any statistically significant difference or correlations among the various groups. These results support the possibility that nerve growth factor mediates the induction of other trophic factors which, in turn, might potentially produce a sprouting response of non-cholinergic fibers that ameliorate the cognitive deficits in impaired, aged rats.

Aging↗
PubMed1994

Synaptotrophic effects of human amyloid beta protein precursors in the cortex of transgenic mice.

The amyloid precursor protein (APP) is involved in Alzheimer's disease (AD) because its degradation products accumulate abnormally in AD brains and APP mutations are associated with early onset AD. However, its role in health and disease appears to be complex, with different APP derivatives showing either neurotoxic or neurotrophic effects in vitro. To elucidate the effects APP has on the brain in vivo, cDNAs encoding different forms of human APP (hAPP) were placed downstream of the neuron-specific enolase (NSE) promoter. In multiple lines of NSE-hAPP transgenic mice neuronal overexpression of hAPP was accompanied by an increase in the number of synaptophysin immunoreactive (SYN-IR) presynaptic terminals and in the expression of the growth-associated marker GAP-43. In lines expressing moderate levels of hAPP751 or hAPP695, this effect was more prominent in homozygous than in heterozygous transgenic mice. In contrast, a line with several-fold higher levels of hAPP695 expression showed less increase in SYN-IR presynaptic terminals per amount of hAPP expressed than the lower expressor lines and a decrease in synaptotrophic effects in homozygous compared with heterozygous offspring. Transgenic mice (2-24 months of age) showed no evidence for amyloid deposits or neurodegeneration. These findings suggest that APP may be important for the formation/maintenance of synapses in vivo and that its synaptotrophic effects may be critically dependent on the expression levels of different APP isoforms. Alterations in APP expression, processing or function could contribute to the synaptic pathology seen in AD.

Amyloid beta-Protein Precursor↗
PubMed1994

Synaptic and neuritic alterations during the progression of Alzheimer's disease.

Extensive synaptic and neuritic alterations in the neocortex and limbic system are characteristically found in Alzheimer's disease (AD). However, it is not known how early in the development of the disease these alterations occur. For the present study, we compared the synaptic and neuritic alterations among cases classified clinically and neuropathologically as early, mild and advanced AD. In early AD there was a 20% loss of synaptophysin-immunoreactive presynaptic terminals in the outer molecular layer of the hippocampal dentate gyrus (but not in the neocortex and entorhinal cortex), accompanied by increased amyloid precursor protein (APP) and Alz50 immunoreactivity in hippocampal and entorhinal cortex pyramidal neurons. These results suggest that abnormal neuronal expression of APP and cytoskeletal proteins in early stages might be involved in the mechanisms of synaptic pathology in AD.

Aged↗
PubMed1994

Topographical distribution of synaptic-associated proteins in the neuritic plaques of Alzheimer's disease hippocampus.

Studies of the molecular composition of the abnormal neuritic processes of the plaques in Alzheimer's disease (AD) have shown that these structures are immunoreactive with antibodies against growth-related molecules, synaptic/axonal proteins, and cytoskeletal proteins. These studies suggest that a subpopulation of abnormal neurites in the plaque are sprouting axons that eventually degenerate. To test this hypothesis further we studied the regional distribution of plaques in the hippocampus using a panel of monoclonal antibodies against synaptic proteins. With these antibodies we found a greater proportion of immunoreactive plaques compared to previous studies where a monoclonal antibody against synaptophysin was used. The most sensitive antibodies to detect neuritic plaques were SP11 and anti-p65, and the largest number of positive plaques was found in the entorhinal cortex and CA1 region. These results further support the theory that synaptic and axonal damage are involved in plaque formation in AD.

Aged↗
PubMed1994

Hippocampal involvement associated with human immunodeficiency virus encephalitis in Mexico.

The objective of the present study was to review the alterations of the central nervous system (CNS) in a group of deceased Mexican patients with acquired immunodeficiency syndrome; autopsies were reviewed with a special emphasis on the damage to the hippocampal formation. Of these 19 deceased patients with acquired immunodeficiency syndrome, nine (47%) had opportunistic infections in the CNS that were accompanied by human immunodeficiency virus encephalitis (HIVE), three (16%) had evidence of opportunistic infections in the brain without HIVE, and two (11%) had HIVE alone. All of the patients who had presented with neurological and neurobehavioral alterations had evidence of HIVE and/or opportunistic infections in the CNS. Of these 19 patients, 11 (58%) had presented with evidence of HIVE (with or without opportunistic CNS infections), as evidenced by the presence of gp41-positive microglial cells in the basal ganglia, neocortex, and hippocampus. The subiculum was the region that displayed the most abundant infiltration by gp41-positive microglial cells. The percentage of cases of acquired immunodeficiency syndrome with HIVE and/or CNS opportunistic infections in our series was similar when compared with that of other series in which similar methods of detection of human immunodeficiency virus in the CNS were used. We conclude that evidence of human immunodeficiency virus-associated lesions in the hippocampal formation might in part explain the selective neuronal alterations in this limbic structure, and we suggest that damage to this circuitry might be in part involved in the cognitive alterations in HIVE.

AIDS-Related Opportunistic Infections↗