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Biomedical subjects

D L Price

Publications and source records attributed to D L Price.

At least 73 records · Page 4Linked to original sources
PubMed1997

The effects of nerve growth factor on spatial recent memory in aged rats persist after discontinuation of treatment.

Nerve growth factor (NGF) infusion significantly reduces spatial recent memory deficits in aged rats, an effect that has great relevance to the treatment of memory impairments characteristic of patients with Alzheimer's disease. The present study was designed to examine whether this NGF-induced improvement in spatial recent memory persists after the discontinuation of NGF treatment, an issue of crucial importance for the potential clinical use of this compound. Spatial recent memory was tested in a Morris water maze delayed nonmatch-to-position task. In addition to memory, sensorimotor skills were also examined. Four- and 22-month-old rats were tested preoperatively, infused intraventricularly with recombinant human NGF or vehicle, and tested both during the 4 week infusion period and during the 4 weeks after discontinuation of the infusion. NGF significantly improved spatial recent memory in 22-month-old rats only, during the 4th week of infusion and for up to 4 weeks after discontinuation of the infusion. Although NGF did not affect overall sensorimotor skills during infusion in either age group, sensorimotor skills were significantly improved both 2 and 4 weeks after discontinuation of infusion in 22-month-old rats. These findings demonstrate that the beneficial effects of NGF on spatial recent memory can persist for up to 1 month after discontinuation of infusion and suggest that NGF can be used intermittently for the treatment of age-associated memory dysfunction and Alzheimer's disease.

Aging↗
PubMed1997

Excitotoxic neuronal death in the immature brain is an apoptosis-necrosis morphological continuum.

Glutamate-induced excitotoxicity is a clinically relevant degenerative process that causes selective neuronal death by mechanisms that remain unclear. Cell death is usually classified as apoptotic or necrotic based on biochemical and morphological criteria. Excitotoxic lesions in the adult rat striatum result in neuronal death associated with apoptotic DNA laddering despite a necrotic appearance of neurons ultrastructurally. This suggests that apoptosis and necrosis may not be mutually exclusive modes of cell death. Here, we characterized normal developmental cell death in the newborn rat brain with respect to DNA fragmentation patterns and ultrastructural morphology to establish a standard for apoptosis in the nervous system, and we concluded that it is essentially indistinguishable from apoptosis described in other tissues. We then investigated whether brain maturity could influence the morphology of neuronal death in vivo in the excitotoxically lesioned newborn rat forebrain. Kainic acid induced DNA laddering and death of neurons exhibiting a variety of morphologies, ranging from necrosis to apoptosis. In neurons that were dying by apoptosis, morphologic changes were characterized by a highly ordered sequence of organelle abnormalities, with swelling of endoplasmic reticulum and Golgi vesiculation preceding most nuclear changes and mitochondrial disruption. We concluded that brain maturity influences the morphologic phenotype of neurodegeneration and that excitotoxic neuronal death in the immature brain is not a uniform event but, rather, a continuum of apoptotic, necrotic, and overlapping morphologies. This excitotoxic paradigm might prove useful for analyzing the mechanisms that govern cell death under physiological and pathological conditions.

Animals↗
PubMed1997

Non-NMDA and NMDA receptor-mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: further evidence for an apoptosis-necrosis continuum.

Apoptosis and necrosis are generally recognized as two distinct pathways of cell death, based on biochemical and morphological characteristics. Despite rapid advances in elucidating molecular mechanisms of cell death, little is known about the morphological progression of death in neurons and the relationship between different mechanisms of neuronal death and the resulting subcellular alterations. With excitotoxicity, a clinically relevant model of neuronal death, apoptotic DNA laddering and morphologic evidence of necrosis can occur simultaneously in the same region of adult brain. Here, we tested the hypothesis that activation of N-methyl-D-aspartic acid (NMDA) and non-NMDA glutamate receptors (GluR) results in a spectrum of morphologically distinct phenotypes of neuronal death, with apoptosis and necrosis as its endpoints. The ultrastructural morphologies of newborn and adult neurons at different times following intrastriatal injections of non-NMDA and NMDA GluR agonists were compared to apoptosis, as established during naturally occurring neuronal death in the developing rat brain. Excitotoxic neuronal death in newborn striatum was morphologically indistinguishable from developmental apoptosis. In the adult, non-NMDA receptor agonist-induced neuronal death was characterized by extensive chromatin condensation that was reminiscent of, but not identical to, apoptosis during normal development. In contrast, quinolinate, an NMDA receptor agonist, produced only minor chromatin clumping and rapid cytoplasmic disintegration, which is suggestive of necrosis. These findings support the concept that degenerative phenotypes of excitotoxically injured neurons are influenced by the degree of brain maturity and GluR subtype stimulation, independent of the severity of excitotoxic insult, along a morphological continuum or gradient ranging from apoptosis to necrosis.

Animals↗
PubMed1997

Fungal colonization of air filters and insulation in a multi-story office building: production of volatile organics.

Secondary air filters in the air-handling units on four floors of a multi-story office building with a history of fungal colonization of insulation within the air distribution system were examined for the presence of growing fungi and production of volatile organic compounds. Fungal mycelium and conidia of Cladosporium and Penicillium spp. were observed on insulation from all floors and both sides of the air filters from one floor. Lower concentrations of volatile organics were released from air filter medium colonized with fungi as compared with noncolonized filter medium. However, the volatiles from the colonized filter medium included fungal metabolites such as acetone and a carbonyl sulfide-like compound that were not released from noncolonized filter medium. The growth of fungi in air distribution systems may affect the content of volatile organics in indoor air.

Acetone↗
PubMed1997

ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions.

High levels of familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 mutants G93A and G37R were previously shown to mediate disease in mice through an acquired toxic property. We report here that even low levels of another mutant, G85R, cause motor neuron disease characterized by an extremely rapid clinical progression, without changes in SOD1 activity. Initial indicators of disease are astrocytic inclusions that stain intensely with SOD1 antibodies and ubiquitin and SOD1-containing aggregates in motor neurons, features common with some cases of SOD1 mutant-mediated ALS. Astrocytic inclusions escalate markedly as disease progresses, concomitant with a decrease in the glial glutamate transporter (GLT-1). Thus, the G85R SOD1 mutant mediates direct damage to astrocytes, which may promote the nearly synchronous degeneration of motor neurons.

ATP-Binding Cassette Transporters↗
PubMed1997

Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins.

Missense mutations in two related genes, termed presenilin 1 (PS1) and presenilin 2 (PS2), cause dementia in a subset of early-onset familial Alzheimer's disease (FAD) pedigrees. In a variety of experimental in vitro and in vivo settings, FAD-linked presenilin variants influence the processing of the amyloid precursor protein (APP), leading to elevated levels of the highly fibrillogenic Abeta1-42 peptides that are preferentially deposited in the brains of Alzheimer Disease (AD) patients. In this report, we demonstrate that transgenic animals that coexpress a FAD-linked human PS1 variant (A246E) and a chimeric mouse/human APP harboring mutations linked to Swedish FAD kindreds (APP swe) develop numerous amyloid deposits much earlier than age-matched mice expressing APP swe and wild-type Hu PS1 or APP swe alone. These results provide evidence for the view that one pathogenic mechanism by which FAD-linked mutant PS1 causes AD is to accelerate the rate of beta-amyloid deposition in brain.

Aging↗
PubMed1997

Hyperaccumulation of FAD-linked presenilin 1 variants in vivo.

Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes can cause Alzheimer's disease in affected members of the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. PS1 encodes an ubiquitously expressed, eight transmembrane protein. PS1 is endoproteolytically processed to an amino-terminal derivative (approximately 27-28 kDa) and a carboxy-terminal derivative (approximately 17-18 kDa). These polypeptides accumulate to saturable levels in the brains of transgenic mice, independent of the expression of PS1 holoprotein. We now document that, in the brains of transgenic mice, the absolute amounts of accumulated N- and C-terminal derivatives generated from the FAD-linked PS1 variants in which Glu replaces Ala at codon 246 (A246E) or Leu replaces Met at codon 146 (M146L) accumulate to a significantly higher degree (approximately 40-50%) than the fragments derived from wild-type PS1. Moreover, the FAD-linked deltaE9 PS1 variant, a polypeptide that is not subject to endoproteolytic cleavage in vivo, also accumulates in greater amounts than the fragments generated from wild-type human PS1. Thus, the metabolism of PS1 variants linked to FAD is fundamentally different from that of wild-type PS1 in vivo.

Actins↗
PubMed1997

Fungal colonization of air filters from hospitals.

Air filters of various types, selected on the basis of discoloration, were collected from the primary and secondary filter banks of the heating, ventilating, and air-conditioning systems in seven hospitals in the eastern United States and examined with direct microscopy for fungal colonization. Microscopic observations and culture results showed that filters from five of the hospitals were colonized with fungi including species of Acremonium, Alternaria, Aspergillus, Cladosporium, Epicoccum, Penicillium, and Rhinocladiella, and a Beauveria-like fungus. Several of these commonly airborne species, e.g., Epicoccum purpurescens (syn. E. nigrum) and Rhinocladiella sp., had not been previously reported to colonize (with conidiogenesis) air filters.

Air Conditioning↗
PubMed1997

Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice.

Missense mutations in the beta-amyloid precursor protein gene (APP) co-segregate with a small subset of autosomal dominant familial Alzheimer's disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid (A beta) peptide and neurodegeneration are principal neuropathological hallmarks. To accurately examine the effect of missense mutations on APP metabolism and A beta production in vivo, we have introduced yeast artificial chromosomes (YACs) containing the entire approximately 400 kbp human APP gene encoding APP harboring either the asparagine for lysine and leucine for methionine FAD substitution at codons 670 and 671 (APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717 (APP(V7171)) or a combination of both substitutions into transgenic mice. We demonstrate that, relative to YAC transgenic mice expressing wild-type APP, high levels of A beta peptides are detected in the brains of YAC transgenic mice expressing human APP(K670N/M671L) that is associated with a concomitant diminution in the levels of apha-secretase-generated soluble APP derivatives. Moreover, the levels of longer A beta peptides (species terminating at amino acids 42/43) are elevated in YAC transgenic mice expressing human APP(V7171). These mice should prove valuable for detailed analysis of the in vivo effects of the APP FAD mutations in a variety of tissues and throughout aging and for testing therapeutic agents that specifically alter APP metabolism and A beta production.

Alzheimer Disease↗
PubMed1997

Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease.

We tested the hypothesis that synaptic defects in the hippocampus of individuals with Alzheimer disease (AD) correlate with the severity of cognitive impairment. Three postmortem groups were studied: controls with normal and stable cognition; cognitively intact subjects with senile plaque densities diagnostic for possible AD (p-AD) and neurofibrillary changes characteristic of early AD (Braak stage III); and individuals with definite AD and neurofibrillary changes typical of incipient to severe AD (Braak stage III, V, or VI). Synaptophysin (a presynaptic vesicle protein) levels were quantified by immunoblotting of synaptic membrane fractions isolated from hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex. Average synaptophysin levels were reduced in hippocampus when comparing definite AD to controls (55%, p < 0.0001), p-AD to control (25%, p < 0.005), and definite AD to p-AD (30%, p < 0.05), but levels in entorhinal cortex, occipital cortex, and caudate nucleus were either unchanged or less significantly altered than in hippocampus. By univariate analysis, hippocampal synaptophysin levels correlated with neuropsychological measurements, including Mini-mental state examination scores (r = 0.83, p < 0.0001) and Blessed scores (r = 0.74, P < 0.001), and with senile plaque densities (r = 0.89, p < 0.0001). We conclude that synaptic abnormalities in the hippocampus correlate with the severity of neuropathology and memory deficit in individuals with AD, and that this defect may predate neuropsychological evidence for cognitive impairment early in AD.

Aged↗
PubMed1997

Solitary fibrous tumor presenting as a symptomatic intraspinal mass: case report.

OBJECTIVE AND IMPORTANCE: Mesenchymal, nonmeningeal tumors of the central and peripheral nervous systems are rare. Specifically, the solitary fibrous tumor, which occurs in both benign and malignant forms, was first described in the pleura and more recently in a number of sites, including the mediastinum, abdomen, upper respiratory tract, nasopharynx, and orbit. It has not, however, previously been known to involve the spine or to induce cord compression. CLINICAL PRESENTATION: We describe the case of a 33-year-old man who presented with back pain, progressive myelopathy, and lower extremity dysesthesias. Imaging studies demonstrated an intradural extramedullary mass at T7-T8. INTERVENTION: At surgery, the lesion was found to be firm, fibrous, intimately apposed to the T8 sensory nerve root but emanating from neither root nor dura. Histologically, the tumor was composed of spindle cells in a storiform pattern with extensive collagen deposition in the intercellular matrix. Immunohistochemistry showed diffuse positive staining of tumor cells for CD34 antigen but negative staining for S100 and EMA, a profile that is consistent with a histopathological diagnosis of solitary fibrous tumor and that effectively rules out meningioma and nerve sheath tumor. CONCLUSION: This is the first report of an intraspinal solitary fibrous tumor, a rare entity that should be included in the differential diagnosis of intradural extramedullary spinal neoplasms.

Adult↗
PubMed1997

Amyotrophic lateral sclerosis and Alzheimer disease. Lessons from model systems.

The human neurodegenerative diseases, including motor neuron disease and Alzheimer's disease (AD), are characterized by a selective involvement of certain regions of the brain/spinal cord and selected populations of neurons. Sporadic amyotrophic lateral sclerosis (ALS) is an age-associated disease with cytoskeletal abnormalities and death of motor neurons; familial ALS (FALS), an autosomal dominant disease linked to mutations in superoxide dismutase 1 (SOD1), is manifested by inclusions and degeneration of motor neurons. Autosomal dominant familial AD (FAD), linked to mutations in presenilin (PS1 and PS2) genes or the amyloid precursor protein (APP) gene, shows brain abnormalities (e.g., neurofibrillary tangles, deposits of .-amyloid A., and death of subsets of neurons) similar to those that occur in sporadic AD, the risk of which is enhanced by the presence of one or two copies of apolipoprotein E4 (apoE4) alleles. To examine the mechanisms of these diseases, investigators have used a variety of animal models, including experimentally produced, spontaneously occurring, or genetically engineered models of disease. Studies of models of degeneration of motor neurons (axotomy) and cytoskeletal abnormalities seen in motor neuron disease (i.e., axonopathy induced by .,.'-iminodipropionitrile (IDPN), hereditary canine spinal muscular atrophy (HCSMA), and neurofilament NF transgenic Tg mice) have demonstrated that NF-filled swellings of axons are related to alterations in the biology of NF transport. Tg mice with SOD1 mutations, which develop the clinical features of FALS, show selective degeneration of motor neurons, which is attributed to the acquisition of toxic properties by mutant SOD1. Models of AD include: aged monkeys that show both cognitive/memory deficits and cellular abnormalities (amyloid deposition/cytoskeletal abnormalities of neurons) in cortex and hippocampus; and Tg mice that express mutant human FAD-linked genes (i.e., APP and PS1) and show increased levels of A.42, amyloid deposits, dystrophic neurites, and local responses of astrocytes and microglia. This review discusses the behavioral/neuropathological features of AD, the results of investigations of mechanisms of disease in model systems, and potential utility of some of these models for testing new therapies.

Alzheimer Disease↗
PubMed1996

Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues.

Mutations in genes encoding related proteins, termed presenilin 1 (PS1) and presenilin 2 (PS2), are linked to the majority of cases with early-onset familial Alzheimer's disease (FAD). To clarify potential function(s) of presenilins and relationships of presenilin expression to pathogenesis of AD, we examined the expression of PS1 and PS2 mRNA and PS1 protein in human and mouse. Semi-quantitative PCR of reverse-transcribed RNA (RT-PCR) analysis revealed that PS1 and PS2 mRNA are expressed ubiquitously and at comparable levels in most human and mouse tissues, including adult brain. However, PS1 mRNA is expressed at significantly higher levels in developing brain. In situ hybridization studies of mouse embryos revealed widespread expression of PS1 mRNA with a neural expression pattern that, in part, overlaps that reported for mRNA encoding specific Notch homologs. In situ hybridization analysis in adult mouse brain revealed that PS1 and PS2 mRNAs are enriched in neurons of the hippocampal formation and entorhinal cortex. Although PS1 and PS2 mRNA are expressed most prominently in neurons, lower but significant levels of PS1 and PS2 transcripts are also detected in white matter glial cells. Moreover, cultured neurons and astrocytes express PS1 and PS2 mRNAs. Using PS1-specific antibodies in immunoblot analysis, we demonstrate that PS1 accumulates as approximately 28 kDa N-terminal and approximately 18 kDa C-terminal fragments in brain. Immunocytochemical studies of mouse brain reveal that PS1 protein accumulates in a variety of neuronal populations with enrichment in somatodendritic and neuropil compartments.

Adult↗
PubMed1996

Ciliary neurotrophic factor stimulates the expression of glial fibrillary acidic protein by brain astrocytes in vivo.

Ciliary neurotrophic factor is a cytokine that has effects on neuronal survival and phenotype in vitro and in vivo. Ciliary neurotrophic factor has also been shown to have effects on microglia and oligodendrocytes in vitro and in vivo. In this study, we demonstrate in vivo effects of ciliary neurotrophic factor on astrocytes in both the injured and uninjured central nervous system. Ciliary neurotrophic factor increases the expression of glial fibrillary acidic protein and induces concomitant morphological changes in central nervous system astrocytes. Messenger RNA for both ciliary neurotrophic factor and the alpha-component of the ciliary neurotrophic factor receptor is demonstrated in the optic nerve, an essentially pure population of central nervous system glia. We also report here that the promoter region of the glial fibrillary acidic protein gene contains sequences thought to confer direct ciliary neurotrophic factor modulation of glial fibrillary acidic protein gene transcription. Although it is thought that astrocytes are a source of endogenous ciliary neurotrophic factor in the central nervous system and that neurons express the alpha-component of the ciliary neurotrophic factor receptor, the results of the present investigation suggest that astrocytes themselves respond to ciliary neurotrophic factor and that ciliary neurotrophic factor may also be important in glial cell-cell interactions.

Animals↗
PubMed1996

Studies on the metabolism and biological function of APLP2.

Amyloid precursor proteins (APP) are a member of a larger family of proteins that include the amyloid precursor-like proteins (APLP) APLPI and APLP2. We have examined the expression and metabolism of APLP2 and document that APLP2 is expressed at high levels in the nervous system and in peripheral tissues. Furthermore, several APLP2 isoforms encoded by alternatively spliced transcripts are posttranslationally modified by a chondroitin sulfate glycosaminoglycan (CSGAG) chain. Furthermore, CSGAG modification is regulated by the insertion of sequences encoded by an alternatively spliced exon. Notably, expression of the CSGAG form of APLP2 appears restricted to embryonic neurons and mature neuronal populations that undergo regeneration, such as olfactory sensory neurons. Thus, differences in posttranslational modifications between the APLP2 isoforms and APP are likely to underlie differences in the regulation and function of these homologues. Our present efforts are directed towards using gene targeting strategies to disrupt the expression of the mouse APP/APLP2 genes to define the normative roles of the encoded molecules in development, plasticity, regeneration, and repair.

Alternative Splicing↗
PubMed1996

Motor neuron disease and model systems: aetiologies, mechanisms and therapies.

The phenotypes of many neurological diseases, including motor neuron disease (amyotrophic lateral sclerosis; ALS) and Alzheimer's disease (AD), are determined by the vulnerabilities of populations of nerve cells and the character/ evolution of cellular abnormalities. Because different cell types respond selectively to individual trophic factors, these factors may be useful in ameliorating pathology in cells that express their cognate receptors. To test therapies for ALS and AD, investigators require model systems. Although there are a variety of models of ALS, two models are particularly attractive: transgenic mice that express human superoxide dismutase 1 (SOD-1) mutations linked to familial ALS develop paralysis associated with a gain of adverse property of the mutant SOD; and axotomy of facial axons in neonatal rats, a manipulation that causes retrograde cell degeneration, which can be ameliorated by several trophic factors.

Animals↗
PubMed1996

Fungal colonization of fiberglass insulation in the air distribution system of a multi-story office building: VOC production and possible relationship to a sick building syndrome.

Complaints characteristic of those for sick building syndrome prompted mycological investigations of a modern multi-story office building on the Gulf coast in the Southeastern United States (Houston-Galveston area). The air handling units and fiberglass duct liner of the heating, ventilating and air conditioning system of the building, without a history of catastrophic or chronic water damage, demonstrated extensive colonization with Penicillium spp and Cladosporium herbarum. Although dense fungal growth was observed on surfaces within the heating-cooling system, most air samples yielded fewer than 200 CFU m-3. Several volatile compounds found in the building air were released also from colonized fiberglass. Removal of colonized insulation from the floor receiving the majority of complaints of mouldy air and continuous operation of the units supplying this floor resulted in a reduction in the number of complaints.

Air Conditioning↗