Biomedical subjects

D L Price

Publications and source records attributed to D L Price.

At least 37 records · Page 2Linked to original sources

PubMed2000

The value of transgenic models for the study of neurodegenerative diseases.

Transgenic animal models are useful in studying the features of APP- and PS1-linked FAD and SOD1-linked FALS. These models help to investigate the nature of the cellular/biochemical/molecular alterations in neural tissue; the character and evolution of neuronal and/or glial abnormalities; the ways mutant proteins cause damage to neurons; and the biochemical pathways associated with cell death. New technologies will help to define changes in a variety of genes/gene products and the events and conformational changes in mutant proteins that are implicated in pathogenic cascades. It is hoped such study will result in novel treatments for testing in transgenic models that can then be translated into new treatments for human neurodegenerative diseases.

Alzheimer Disease↗

PubMed1999

New order from neurological disorders.

The neurological diseases described in this review supplement impact across a wide spectrum of the population. Here, their similarities and differences are highlighted, and common themes of the interactions between basic and clinical sciences for their understanding and treatment are explored.

Animals↗

PubMed1999

Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington's disease brain nuclei.

The protein huntingtin (htt), aggregated in neuronal nuclear inclusions, is pathognomonic of Huntington's disease (HD). Constructs, translated in vitro from the N terminus of htt, containing either polyQ23 from a normal individual, or polyQ41 or polyQ67 from an HD patient, were all soluble. Transglutaminase (TGase) crosslinked these proteins, and the aggregations did not have the staining properties of amyloid. More TGase-catalyzed aggregates formed when the polyglutamine domain of htt exceeded the pathologic threshold of polyQ36. Furthermore, shorter htt constructs, containing 135 aa or fewer, formed more aggregates than did larger htt constructs. TGase activity in the HD brain was increased compared with the control, with notable increases in cell nuclei. The increased TGase activity was brain specific. In lymphoblastoid cells from HD patients, TGase activity was decreased. TGase-mediated crosslinking of htt may be involved in the formation of the nonamyloidogenic nuclear inclusions found in the HD brain. The staining properties of nuclear inclusions in the HD brain revealed that they were not amyloid.

Adult↗

PubMed1999

Evidence that nerve growth factor influences recent memory through structural changes in septohippocampal cholinergic neurons.

We compared, in 4- and 23-month-old Fischer-344 rats, the effects of nerve growth factor (NGF) on basal forebrain cholinergic neurons with behavioral performance in acetylcholine-dependent memory tasks (recent and reference memory). Noncholinergic monoamine markers in target fields of cholinergic neurons were also investigated. We found that NGF has contrasting effects on recent memory in the two age groups in causing improvement in aged rats and deterioration in young rats. In addition, NGF caused significant increase in the size of cholinergic perikarya in all sectors of the basal nucleus complex (BNC). Higher doses of NGF were required to produce hypertrophy in aged animals, a pattern consistent with a lower sensitivity to NGF of aged cholinergic neurons. Analysis of covariance showed that the behavioral effects of NGF were eliminated after covarying out the hypertrophy of cholinergic perikarya. Therefore, NGF causes hypertrophy of cholinergic perikarya regardless of age, and this neurobiological measure correlates with the effects of NGF on recent memory. Reference memory improved moderately only in old rats. This mild effect covaried with an increase in choline acetyltransferase activity in neocortex. Cortical terminal fields of noradrenergic and serotoninergic pathways were not affected by NGF. Taken together, our results indicate that NGF influences recent memory in an age- and transmitter-specific fashion. We postulate that the direct cause of the effects of NGF on memory is not perikaryal hypertrophy per se but rather an increased density of terminals, which always accompanies perikaryal hypertrophy. Although these results continue to support the use of NGF for the treatment of Alzheimer's disease, they raise questions regarding the therapeutic role of NGF for degeneration of BNC neurons occurring in young age.

Animals↗

PubMed1999

Sanitation of wallboard colonized with Stachybotrys chartarum.

Sections (8 cm2) of unused, nonsterile gypsum wallboard (dry wall) were inoculated with varying densities (10(4) to approximately 10(8)/ml) of conidia from 14- to 21-day cultures of Stachybotrys chartarum grown on cellulose agar. The sections were permitted to air dry and were placed into vessels with 86% or 92% RH and incubated at 22-25 degrees C for up to 12 weeks. The moisture content of the dryboard increased from near 10% to over 35%. Selected sections with confluent surface growth, mainly of S. chartarum, were obtained within 3 weeks. Sections were cleaned with a quaternary or quaternary and chlorine dioxide or a concentrated oxygen-saline solution and treated, in some cases, with a preservative system and returned to humidity vessels. Reemergence of S. chartarum from inoculated and treated surfaces occurred within 5 weeks only with sections treated with the quaternary alone. Other fungi, mostly species of Aspergillus, Chaetomium and Penicillium, slowly colonized (between 9-12 weeks) at least some areas of most treated surfaces and most uninoculated control surfaces. Stachybotrys chartarum was also found on several sections of uninoculated controls. Sections treated with a quaternary/acrylic and placed in a dynamic challenging chamber remained visually free of colonized fungi for over 90 days. These studies indicate that control samples of uninstalled wallboard, available from local distributors, can contain a baseline bioburden, including S. chartarum, that will colonize surfaces under high humidity conditions. Sanitation and preservation treatment of the wallboard can markedly delay regrowth of these fungi, particularly of S. chartarum.

Chlorine Compounds↗

PubMed1999

Kearns-Sayre syndrome with features of Pearson's marrow-pancreas syndrome and a novel 2905-base pair mitochondrial DNA deletion.

Kearns-Sayre syndrome (KSS) and Pearson's marrow-pancreas syndrome (PMPS) are rare disorders caused by the same molecular defect, one of several deletion mutations in mitochondrial DNA (mtDNA). KSS is an encephalomyopathy with ophthalmoplegia, retinal degeneration, ataxia, and endocrine abnormalities. PMPS is a disorder of childhood characterized by refractory anemia, vacuolization of bone marrow cells, and exocrine pancreas dysfunction. Children with PMPS that have a mild phenotype, or are supported through bone marrow failure, often develop the encephalomyopathic features of KSS. The subject of numerous reports in the neuromuscular, genetic, and pediatric literature in recent years, very few cases of either disorder have ever been studied at autopsy. We report the results of our studies of a patient with clinically documented KSS who presented with renal dysfunction and was found to have a novel mtDNA deletion and degenerative changes in the central nervous system, retina, skeletal muscle, and pancreas.

Adolescent↗

PubMed1999

Presynaptic markers of cholinergic function in the rat brain: relationship with age and cognitive status.

The nature of age-related changes in cholinergic function and their relationship to age-related behavioral decline were examined in the present study. Male Fischer-344 rats of four ages (four, 11, 17 and 23 months) were tested in a battery of cognitive tasks. Discrete microdissections of brain areas involved in cognitive function were performed, and activity of choline acetyltransferase and levels of hemicholinium-3 binding were determined to assess the integrity of cholinergic innervation. Age-related changes in cholinergic markers occurred predominantly in the medial septal area and its target areas (hippocampus and cingulate cortex), and were also present in the posterior caudate. However, most of the age-related changes in cholinergic markers were already present at ages at which behavioral impairment was not yet maximal. There were some consistent correlations between behavioral and neurochemical measures, independent of age, but these accounted for relatively small proportions of variance in behavioral performance. For most of these correlations, lower levels of presynaptic cholinergic markers were related to better behavioral performance. In brain areas in which correlations changed with age, lower levels of presynaptic cholinergic markers were associated with better performance in young rats, whereas higher levels were associated with better performance in aged rats. Recent lesion studies using a toxin selective for basal forebrain cholinergic neurons have suggested that these neurons do not play as central a role in learning and memory in young and aged animals as was previously thought. When considered in this context, the present results suggest that preserved cholinergic function in old age might act indirectly to sustain cognitive ability. Changes in cholinergic function may represent one of a number of age-related neurobiological events that underlie behavioral impairments, or may be a permissive factor for other age-related processes that are more directly responsible for cognitive impairments.

Acetylcholine↗

PubMed1999

Episodic ataxia/myokymia mutations functionally expressed in the Shaker potassium channel.

Episodic ataxia type 1 is a rare, autosomal dominant neurological disorder caused by missense mutations of the Kv1.1 gene from the Shaker K+ channel subfamily. To study the functional effects of the disease-causing mutations in a robust K+ channel background, we introduced seven different episodic ataxia type 1 substitutions into the corresponding, conserved residues of the Shaker K+ channel. K+ channel currents expressed in Xenopus oocytes were studied by electrophysiology. All episodic ataxia type 1 mutations produced functional K+ channels. In a Shaker N-terminal deletion mutant with fast inactivation removed, current amplitudes were significantly reduced in channels harboring an episodic ataxia type 1 mutation. Six of the seven mutations also showed depolarizing shifts (+9 to +36 mV) in the conductance voltage dependence. One mutation (F307I) shifted the midpoint of the conductance-voltage relationship by 23 mV in the hyperpolarizing direction. Episodic ataxia type 1 mutations were also expressed in ShakerH4 with intact N-terminal inactivation. In this construct, current amplitudes for episodic ataxia type 1 mutants were not significantly different from wild-type channels. All mutations altered the voltage range of steady-state inactivation; most changes were coupled to the changes in activation gating. Some episodic ataxia type 1 mutants also caused significant changes in the kinetics of N-type (F307I, E395D) or C-type (F307I, E395D, V478A) inactivation. These results suggest that episodic ataxia type 1 mutations may change K+ channel function by two mechanisms: (i) reduced channel expression and (ii) altered channel gating.

Animals↗

PubMed1999

Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA.

Dentatorubral and pallidoluysian atrophy (DRPLA) is a member of a family of progressive neurodegenerative diseases caused by polyglutamine repeat expansion. Transgenic mice expressing full-length human atrophin-1 with 65 consecutive glutamines exhibit ataxia, tremors, abnormal movements, seizures, and premature death. These mice accumulate atrophin-1 immunoreactivity and inclusion bodies in the nuclei of multiple populations of neurons. Subcellular fractionation revealed 120 kDa nuclear fragments of mutant atrophin-1, whose abundance increased with age and phenotypic severity. Brains of DRPLA patients contained apparently identical 120 kDa nuclear fragments. By contrast, mice overexpressing atrophin-1 with 26 glutamines were phenotypically normal and did not accumulate the 120 kDa fragments. We conclude that the evolution of neuropathology in DRPLA involves proteolytic processing of mutant atrophin-1 and nuclear accumulation of truncated fragments.

Adolescent↗

PubMed1999

The copper chaperone CCS is abundant in neurons and astrocytes in human and rodent brain.

Copper trafficking in mammalian cells is highly regulated. CCS is a copper chaperone that donates copper to the antioxidant enzyme copper/zinc superoxide dismutase 1 (SOD 1). Mutations of SOD1 are responsible for approximately 20% of familial amyotrophic lateral sclerosis (FALS). Monospecific antibodies were generated to evaluate the localization and cellular distribution of this copper chaperone in human and mouse brain as well as other organs. CCS is found to be ubiquitously expressed by multiple tissues and is present in particularly high concentrations in kidney and liver. In brain and spinal cord, CCS was found throughout the neuropil, with expression largely confined to neurons and some astrocytes. Like SOD1, CCS immunoreactivity was intense in Purkinje cells, deep cerebellar neurons, and pyramidal cortical neurons, whereas in spinal cord, CCS was highly expressed in motor neurons. In cortical neurons, CCS was present in the soma and proximal dendrites, as well as some axons. Although the distribution of CCS paralleled that of SOD1, there was a 12-30-fold molar excess of SOD1 over CCS. That both SOD1 and CCS are present, together, in cells that degenerate in ALS also emphasizes the potential role of CCS in mutant SOD1-mediated toxicity.

Amyotrophic Lateral Sclerosis↗

PubMed1999

Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin.

Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1-17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q. These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.

Animals↗

PubMed1999

Chemical applications of neutron scattering.

Neutron scattering represents a versatile technique for chemists, as it explores the structure and dynamics of materials at the atomic scale. This review gives an outline of the neutron scattering formalism and describes diffraction and inelastic and quasielastic scattering techniques. Applications to chemistry are illustrated by examples from recent work on crystalline and liquid organic materials, including heterogeneous systems, bulk polymers and polymer solutions. There is particular emphasis on systems where hydrogen bonding plays a significant role. With more powerful sources and improved instrumentation in prospect, there is considerable potential for future extension of these methods to increasingly complex materials.

Journal Article↗

PubMed1998

Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path.

Amyloid deposition is a neuropathological hallmark of Alzheimer's disease. The principal component of amyloid deposits is beta amyloid peptide (Abeta), a peptide derived by proteolytic processing of the amyloid precursor protein (APP). APP is axonally transported by the fast anterograde component. Several studies have indicated that Abeta deposits occur in proximity to neuritic and synaptic profiles. Taken together, these latter observations have suggested that APP, axonally transported to nerve terminals, may be processed to Abeta at those sites. To examine the fate of APP in the CNS, we injected [35S]methionine into the rat entorhinal cortex and examined the trafficking and processing of de novo synthesized APP in the perforant pathway and at presynaptic sites in the hippocampal formation. We report that both full-length and processed APP accumulate at presynaptic terminals of entorhinal neurons. Finally, we demonstrate that at these synaptic sites, C-terminal fragments of APP containing the entire Abeta domain accumulate, suggesting that these species may represent the penultimate precursors of synaptic Abeta.

Amyloid beta-Peptides↗

PubMed1998

Genetic neurodegenerative diseases: the human illness and transgenic models.

Review The neurodegenerative disorders, a heterogeneous group of chronic progressive diseases, are among the most puzzling and devastating illnesses in medicine. Some of these disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, the prion diseases, and Parkinson's disease, can occur sporadically and, in some instances, are caused by inheritance of gene mutations. Huntington's disease is acquired in an entirely genetic manner. Transgenic mice that express disease-causing genes recapitulate many features of these diseases. This review provides an overview of transgenic mouse models of familial amyotrophic lateral sclerosis, familial Alzheimer's disease, and Huntington's disease and the emerging insights relevant to the underlying molecular mechanisms of these diseases.

Alzheimer Disease↗

PubMed1998

Protective effect of neurofilament heavy gene overexpression in motor neuron disease induced by mutant superoxide dismutase.

To investigate the role of neurofilaments in motor neuron disease caused by superoxide dismutase (SOD1) mutations, transgenic mice expressing a amyotrophic lateral sclerosis-linked SOD1 mutant (SOD1(G37R)) were mated with transgenic mice expressing human neurofilament heavy (NF-H) subunits. Unexpectedly, expression of human NF-H transgenes increased by up to 65%, the mean lifespan of SOD1(G37R) mice. Microscopic examination corroborated the protective effect of NF-H protein against SOD1 toxicity. Although massive neurodegeneration occurred in 1-yr-old mice expressing SOD1(G37R) alone, spinal root axons and motor neurons were remarkably spared in doubly SOD1(G37R);NF-H-transgenic littermates.

Amyotrophic Lateral Sclerosis↗

PubMed1998

Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length.

Huntington's disease (HD) is caused by CAG triplet repeat expansion in IT15 which leads to polyglutamine stretches in the HD protein product, huntingtin. The pathological hallmark of HD is the degeneration of subsets of neurons, primarily those in the striatum and neocortex. Specific morphological markers of affected cells have not been identified in patients with HD, although a unique itranuclear inclusion was recently reported in neurons of transgenic animals expressing a construct encoding the N-terminal part (including the glutamine repeat) of huntingtin (Davies et al., 1997). In order to understand the importance of this finding, we sought for comparable nuclear abnormalities in autopsy material from patients with HD. In all 20 HD cases examined, anti-ubiquitin and N-terminal huntingtin antibodies identified itranuclear inclusions in neurons and the frequency of these lesions correlated with the length of the CAG repeat in IT15. In addition, examination of material from the related HD-like triplet repeat disorder, dentatorubral and pallidoluysian atrophy, also revealed intranuclear neuronal inclusions. These findings suggest that intranuclear inclusions containing protein aggregates may be common feature of the pathogenesis of glutamine repeat neurodegenerative disorders.

Adolescent↗

PubMed1998

Stable association of presenilin derivatives and absence of presenilin interactions with APP.

Mutations in two related genes, presenilin 1 and 2 presenilin 2 (PS1 and PS2), cosegregate with Alzheimer's disease. PS1 and PS2 are highly homologous polytopic membrane proteins that are subject to endoproteolytic cleavage in vivo. The resulting N- and C-terminal derivatives are the preponderant PS-related species that accumulate in cultured cells and tissue. In earlier studies, we demonstrated that PS1 N- and C-terminal derivatives accumulate to 1:1 stoichiometry and that the absolute levels of fragments are established by a tightly regulated and saturable mechanism. These findings led to the suggestion that the levels of PS1 derivatives might be determined by their association with limiting cellular components. In this study, we use in situ chemical cross-linking and coimmunoprecipitation analyses to document that the N- and C-terminal derivatives of either PS1 or PS2 can be coisolated. Moreover, and in contrast to published reports which documented that PS1 and PS2 form stable heteromeric assemblies with the beta-amyloid precursor protein (APP), we have failed to provide evidence for physiological complexes between PS1 and PS2 holoproteins or their derivatives with APP.

Alzheimer Disease↗

PubMed1998

Axonal transport of mutant superoxide dismutase 1 and focal axonal abnormalities in the proximal axons of transgenic mice.

Superoxide dismutase 1 (SOD1), a ubiquitously expressed enzyme, detoxifies superoxide radicals and participates in copper homeostasis. Mutations in this enzyme have been linked to a subset of autosomal dominant cases of familial amyotrophic lateral sclerosis (FALS), a disorder characterized by selective degeneration of motor neurons. Transgenic mice expressing FALS mutant human (Hu) SOD1 at high levels develop a motor neuron disease, indicating that mutant Hu SOD1 gains properties that are particularly toxic to motor neurons. In this report, we demonstrate that transgenic mice expressing Hu SOD1 with the G37R FALS mutation, but not mice expressing wild-type enzyme, develop focal increases in immunoreactivity in the proximal axons of spinal motor neurons. This SOD1 immunoreactivity and immunoreactivity to hypophosphorylated neurofilament H epitopes are found adjacent to small vacuoles in axons. Using metabolic radiolabeling methods, we show that mutant G37R HuSOD1 as well as endogenous mouse SOD1 are transported anterograde in slow component b in motor and sensory axons of the sciatic nerve. Together, these findings suggest that anterogradely transported mutant SOD1 may act locally to damage motor axons.

Animals↗