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L C Walker

Publications and source records attributed to L C Walker.

At least 73 records · Page 4Linked to original sources
PubMed1991

Amyloid-related proteins and nerve growth factor in Alzheimer's disease and animal models.

Alzheimer's disease (AD), the most common cause of dementia in adult life, is characterized by the deposition of amyloid in brain parenchyma and the degeneration of specific populations of nerve cells, including cholinergic neurons in the basal forebrain. In this review, we first outline studies of cellular and molecular events that lead to age-associated deposition of amyloid in the brains of nonhuman primates and then describe investigations of the effect of treatment with nerve growth factor (NGF) on experimentally induced abnormalities in cholinergic neurons of the basal forebrain. These studies of amyloidogenesis and the efficacy of trophic factors on specific groups of experimentally damaged neurons provide information about issues central to understanding the pathogenesis and treatment of human degenerative diseases, including AD.

Alzheimer Disease↗
PubMed1991

Aged non-human primates: an animal model of age-associated neurodegenerative disease.

Aged non-human primates develop age-associated behavioral and brain abnormalities similar to those that occur in aged humans and, to a greater extent, in individuals with Alzheimer's disease. Declines in performance on cognitive and memory tasks begin at the monkey equivalent of late-middle life. As occurs in elderly humans, significant differences have been demonstrated in levels of performance between animals within older age groups. The brains of old monkeys show degenerative changes in neurons, abnormal axons and neurites (particularly in telencephalic areas), and deposits of amyloid in senile plaques and around blood vessels. Moreover, in some older animals, decrements occur in markers of specific neurotransmitter circuits, including the basal forebrain cholinergic system. It has been suggested that alterations in these cholinergic neurons contribute to the memory deficits that occur in older individuals. Because axotomy-induced retrograde degeneration of these neurons can be prevented by the administration of nerve growth factor, we have begun studies to determine whether administration of nerve growth factor improves performance of aged animals on memory tasks. This review describes the complementary nature of studies of non-human primates and human subjects, illustrating how these investigations can clarify factors that influence behavior and brain biology in age-associated diseases.

Aging↗
PubMed1990

Amyloid in the brains of aged squirrel monkeys.

In this immunocytochemical study, the brains of nine squirrel monkeys (Saimiri sciureus), ranging from 8 to 27 years of age, were examined for the presence and distribution of beta/A4 amyloid, a 4-kilodalton peptide. In aged squirrel monkeys, amyloid is associated primarily with intracerebral and meningeal capillaries and arterioles and occurs to a lesser degree as small and/or diffuse deposits in the neural parenchyma and in the dense cores of senile plaques. Cerebrovascular amyloid is found primarily in neocortex, amygdala, and septum verum and is rare or nonexistent in other subcortical gray structures, white matter, cerebellum, and spinal cord; this pattern of localization is comparable to that in humans with cerebral amyloid angiopathy. There is a significant correlation between cerebrovascular and parenchymal deposits of amyloid. However, cerebrovascular amyloid is always the most abundant form in squirrel monkeys, even in cases of severe cerebral amyloidosis. In contrast to squirrel monkeys, aged rhesus monkeys (Macaca mulatta) develop mostly parenchymal deposits of amyloid and have relatively less vascular amyloid. This species difference in the histological distribution of amyloid suggests that separate mechanisms may influence the accumulation of amyloid in cerebral blood vessels and in the neural parenchyma. These data also indicate that the squirrel monkey can serve as a model for investigations of cerebrovascular amyloidosis.

Aging↗
PubMed1990

AIDS pathogenesis: HIV envelope and its interaction with cell proteins.

The immune deficiency induced by HIV has its origin in the interaction of the outer envelope glycoprotein gp120/gp41 with receptors present on human immunocytes. Virus binding to cells, virus entry and subsequent compartmentalization resulting in productive infection depends on the interaction of gp120/gp41 with CD4 and other accessory molecules. Gp120 and HIV are markedly immunosuppressive of T-cell responses and, in addition, HIV can functionally delete antigen responsiveness of T cells. Abolition of CD4 binding, by denaturation of gp120, allows study of T-cell epitopes in gp120 and shows the denatured molecule is highly immunogenic even in naive subjects (F. Manca, unpublished). The gp120-binding site of CD4 is shared with MHC class II molecules and the reaction of antibodies within this region of CD4 induces conformational changes that may be significant for virus entry into cells or for syncytial formation. The HIV envelope contains sites of sequence homology with monomorphic human MHC class II sites that do not appear to be naturally immunogenic in humans. In addition to the properties of gp120, it is hypothesized that HIV envelope may also represent an 'alloepitope' of class II to the human T-cell repertoire, and is therefore able to induce a chronic allogeneic response not dissimilar to experimentally induced GVHD. These features are of potential importance both for primary vaccination against HIV, and for the long-term treatment of HIV seropositive patients. Induction of effective T-cell responses to gp120 require use of a denatured or otherwise modified product lacking CD4-binding capacity. The potential distortion of the TCR repertoire by the class-II-homologous and CD4-interactive sequences must be assessed.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1990

Neuronal responses to injury and aging: lessons from animal models.

Alzheimer's disease (AD), the most common type of adult-onset dementia, is characterized by a variety of brain abnormalities, including degeneration of certain populations of nerve cells, alterations in the neuronal cytoskeleton, and the abnormal deposition of amyloid within brain parenchyma. Pathogenetic processes that lead to these brain abnormalities are difficult to study in humans. Recently, investigators have begun to utilize animal models to examine some of the mechanisms that cause cellular/molecular alterations in transmitter systems, cytoskeletal elements, and APP. These investigations have helped to clarify issues related to the lesions that occur in aged humans and individuals with AD.

Aging↗
PubMed1990

Anti-CD4 autoantibodies and screening for anti-idiotypic antibodies to anti-CD4 monoclonal antibodies in HIV-seropositive people.

The cell-surface antigen CD4 is the major receptor for HIV. Anti-CD4 autoantibodies and anti-idiotypic antibodies to murine monoclonal anti-CD4 antibodies have been described in HIV-infected people. Ninety-seven sera from HIV-infected people at all stages of disease were examined for the presence of anti-idiotypic antibodies to three anti-CD4 monoclonal antibodies. None were found. The same sera were screened for antibodies reactive with soluble CD4, and five (5.2%) were positive. These antibodies did not recognize native CD4, and it is thought unlikely that they arise as anti-idiotypes to anti-gp120 antibodies.

Antibodies, Anti-Idiotypic↗
PubMed1990

Neuronal disorders: studies of animal models and human diseases.

The peripheral nervous system and the central nervous system (CNS) are comprised of assemblies of neurons that communicate via electrical and chemical signals. Different disease processes selectively affect specific populations of neurons and/or specific cell functions (i.e., "selective vulnerability" of neurons is a principal determinant of phenotypes of disease). New cellular and molecular biological approaches have begun to clarify some of the mechanisms of selective cell injury in human diseases and their animal models. Following a brief review of the normal biology of nerve cells, we use illustrations drawn from studies of experimental and human diseases to discuss the mechanisms of structural/chemical abnormalities that occur in a variety of neuronal disorders.

Animals↗
PubMed1990

Laminar organization and age-related loss of cholinergic receptors in temporal neocortex of rhesus monkey.

Using in vitro receptor autoradiography, the distributions of cholinergic muscarinic [3H-N-methyl scopolamine (NMS), 3H-pirenzepine (PZ), and 3H-oxotremorine-M (OXO-M)] and nicotinic [3H-acetylcholine (ACh)] receptors were mapped in the temporal cortices of rhesus monkeys (Macaca mulatta) ranging from 2-22 years of age. Although high-affinity 3H-PZ, low-affinity 3H-NMS binding (M1 sites) and high-affinity 3H-OXO-M, high-affinity 3H-NMS binding (M2 sites) occurred across all layers of the temporal neocortex, the laminar distribution of M1 and M2 receptor binding sites was different. M1 muscarinic receptor binding was concentrated in layers II and III, whereas M2 muscarinic receptor binding was greatest in layers IV and V. The concentration of both muscarinic (M1 and M2) and nicotinic receptor binding sites declined with increasing age, and decrements were uniform across all cortical layers. This investigation provides evidence for a decrease in cholinergic receptor binding with age in temporal cortices of rhesus monkeys. Moreover, these changes appear to precede previously reported age-associated memory deficits and neuropathological changes that occur in this species.

Aging↗
PubMed1989

Compartment-specific changes in the density of choline and dopamine uptake sites and muscarinic and dopaminergic receptors during the development of the baboon striatum: a quantitative receptor autoradiographic study.

In the fetal and young primate neostriatum, cholinergic and dopaminergic markers show patches of high density surrounded by a lower-density matrix. In the adult, the same markers display the opposite pattern, a lower density in striosomes, surrounded by a higher-density matrix. In order to understand the developmental sequences leading to the adult compartmental organization of the primate neostriatum, a quantitative technique was used to study the ontogeny of pre- and postsynaptic components of cholinergic and dopaminergic neurons in baboon caudate nucleus and putamen. The development of specific uptake mechanisms for choline and dopamine and receptors was studied by means of quantitative autoradiography of the specific binding of [3H]-hemicholinium-3 [( 3H]-HC3) and [3H]-mazindol [( 3H]-MAZ) to the choline and dopamine uptake systems, respectively. [3H]-pirenzepine [( 3H]-PIR) was used to label M1 muscarinic receptors and [3H]-spiroperidol [( 3H]-SPI) was used to label striatal dopamine D2 receptors. Serial sections were used for each ligand to determine the precise anatomical relationships between the binding patterns of the different markers. Our aim was to determine whether the adult striosomal distribution of the binding sites studied was due to 1) a selective decrease in patch/striosomal binding density or 2) a selective increase in matrix binding density. Our studies show that a postnatal decrease in the density of [3H]-HC3 sites in the patch/striosomes and an increase in the matrix density of [3H]-MAZ sites are the primary, but not the sole, changes in the compartmental distribution of these sites leading to the adult striosomal organization of the striatal cholinergic and dopaminergic innervation. D2 receptors follow the general developmental pattern of [3H]-MAZ and [3H]-HC3, changing their density of distribution in both compartments during the developmental period examined. In addition, M1 muscarinic receptors already display their adult pattern in the newborn baboon striatum, and therefore represent one of the first neurochemical makers to adopt its mature organization.

Animals↗
PubMed1989

GABAergic neurons in the primate basal forebrain magnocellular complex.

Hybridization histochemistry was used to detect messenger ribonucleic acid (mRNA) coding for glutamic acid decarboxylase, the synthesizing enzyme for gamma-aminobutyric acid (GABA), in neurons of the nucleus basalis of Meynert and nucleus of the diagonal band of Broca of one rhesus monkey and 4 baboons. GABAergic neurons were distributed among the unlabeled large, hyperchromic Nissl-stained neurons characteristic of this basal forebrain magnocellular complex, although they were infrequent within the dense islands of large cells. Most GABAergic cells were small to medium in size, but some were large and hyperchromic. These findings demonstrate a heterogeneous population of presumably inhibitory neurons in the basal forebrain magnocellular complex of primates.

Animals↗
PubMed1989

Aberrant phosphorylation of neurofilaments accompanies transmitter-related changes in rat septal neurons following transection of the fimbria-fornix.

Lesions of the fimbria-fornix (FF) have been reported to cause retrograde changes in neurons of the medial septal nucleus (MSN). To analyze the nature and time course of these events, we investigated changes in cytoskeletal elements (phosphorylated and non-phosphorylated neurofilament (NF) proteins) and transmitter-related enzymes (choline acetyltransferase (ChAT) in MSN neurons following FF transection. During the first week postlesion, ChAT immunoreactivity and size of many perikarya were reduced. Irregular, swollen cholinergic fibers appeared first at postlesion day 2 in caudal septum and soon spread rostrally, reaching rostral septum by day 7. A few perikarya developed abnormal accumulations of phosphorylated NFs. At postlesion days 7-10, many neurons did not stain for ChAT. Phosphorylated NFs were present in many perikarya. At this time, cell loss was apparent in Nissl-stained material. Cholinergic cell loss continued through postlesion weeks 6-8 but at a much slower rate than during the first week. Phosphorylated NF accumulations in MSN perikarya persisted until postlesion week 6, disappearing thereafter. Double-immunostaining procedures showed that MSN neurons expressed both ChAT and phosphorylated NF immunoreactivity at postlesion day 3; however, at days 7 and 14, cells that accumulated phosphorylated NFs did not stain for ChAT. The results of this study indicate that FF transection leads to perikaryal shrinkage with loss of ChAT immunoreactivity, perikaryal phosphorylation of NFs, cholinergic fiber abnormalities, and cell loss. Recent evidence suggests that reduction of transmitter markers and aberrant phosphorylation of NFs may be involved in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. Therefore, FF transection provides a useful animal model for further investigations of complex disorders of the central nervous system that involve degeneration of transmitter-specific pathways.

Animals↗
PubMed1989

Peptidergic neurons in the basal forebrain magnocellular complex of the rhesus monkey.

The basal forebrain magnocellular complex of primates is defined by the presence of large, hyperchromic, usually cholinergic neurons in the nucleus basalis of Meynert and nucleus of the diagonal band of Broca. Because there is growing evidence for noncholinergic neuronal elements in the basal forebrain complex, five neuropeptides and the enzyme choline acetyltransferase were studied immunocytochemically in this region of rhesus monkeys. Galaninlike immunoreactivity coexists with choline-acetyl-transferase-like immunoreactivity in most large neurons and in some smaller neurons of the primate nucleus basalis and nucleus of the diagnonal band. Four other peptides show immunoreactivity in more limited regions of the basal forebrain complex, usually in separate smaller, noncholinergic neurons. Numerous small, somatostatinlike-immunoreactive neurons occupy primarily anterior and intermediate segments of the nucleus basalis, especially laterally and ventrally. Somewhat fewer, small neuropeptide Y-like-immunoreactive somata are found in the same regions. Neurons that show neurotensinlike immunoreactivity are slightly larger than cells that contain immunoreactivity for somatostatin or neuropeptide Y, but these neurons also occur mainly in anterior and intermediate parts of the nucleus basalis. Overall, the usually small, leucine-enkephalin-like-immunoreactive neurons are infrequent in the basal forebrain complex and are most abundant in the rostral intermediate nucleus basalis. Thus, neurons that appear to contain somatostatin, neuropeptide Y, neurotensin, or enkephalin mingle with cholinergic/galaninergic neurons only in some subdivisions of the nucleus basalis/nucleus of the diagonal band, and their distributions suggest that some of these small neurons could be associated with structures that overlap with cholinergic neurons of the labyrinthine basal forebrain magnocellular complex. We also have found light microscopic evidence for innervation of basal forebrain cholinergic neurons by boutons that contain galanin-, somatostatin-, neuropeptide Y-, neurotensin-, or enkephalinlike immunoreactivity. The origins and functions of these putative synapses remain to be determined.

Animals↗
PubMed1989

Serotoninergic neurites in senile plaques in cingulate cortex of aged nonhuman primate.

In immunocytochemical studies, a polyclonal antiserotonin antibody was used to visualize fibers within the cingulate cortex of young and aged rhesus monkeys. Intricate and distinct patterns of serotoninergic processes were seen in anterior and posterior segments of cingulate cortex (Brodmann areas 24 and 23). In these regions of cortex, many multivaricose serotonin-immunoreactive axonal swellings were identified, and some of these immunostained neurites were associated with deposits of amyloid. These observations suggest that serotoninergic processes are involved in the formation of senile plaques in neocortex of aged macaques.

Aging↗
PubMed1989

Distribution of a set of idiotopes detected by a monoclonal antibody panel in 42 cases of chronic lymphocytic leukaemia: definition of potential targets for immunotherapy.

Using a panel of 14 monoclonal V region reactive antibodies generated against a single IgG1 lambda paraprotein we have identified shared idiotopes in a group of 42 patients with chronic lymphocytic leukaemia (CLL). The specificity of cellular staining by indirect immunoperoxidase was confirmed in the majority of cases by an ELISA assay using secreted idiotypic immunoglobulin. In a few cases weak cellular binding by the panel antibodies could not be confirmed as specific for immunoglobulin. Four monoclonal antibodies specific for lambda chain determinants reacted with 5-29% of lambda expressing CLLs but the significance of this is uncertain as the antibodies may be recognizing one of the commoner V lambda subgroups. Two antibodies, which are only weakly reactive with normal serum immunoglobulin, detected heavy chain associated idiotopes which were expressed by 7% and 14% of CLL cases. One of these antibodies detects an idiotope which was expressed significantly more frequently by CLL associated immunoglobulin than by a panel of paraproteins. Such preferentially expressed idiotopes may be useful in investigating the biology of this disorder as well as providing attractive targets for immunotherapy.

Antibodies, Monoclonal↗
PubMed1988

Developmental changes of neuropeptides and amino acids in baboon cortex.

The pattern of developmental changes in concentrations of substance P, somatostatin and neuropeptide Y immunoreactivity and amino acids was studied in baboon cortex. Samples of occipital or frontal neocortex were obtained from preterm (100-105 days gestation), near-term (170-176 days gestation), and young adult animals. Substance P concentrations were low at preterm, highest at near-term, and then declined to adult levels. Neuropeptide Y and somatostatin immunoreactivity increased steadily across the three age groups. Concentrations of aspartate and gamma-aminobutyric acid (GABA) also increased progressively from preterm to adulthood, whereas glutamate concentrations showed small increases that were not statistically significant. Concentrations of taurine and alanine were highest preterm and declined progressively to adulthood. Levels of neuropeptides and amino acids show distinct patterns of change during development of neocortex in the baboon.

Amino Acids↗
PubMed1988

Topographic, non-collateralized basal forebrain projections to amygdala, hippocampus, and anterior cingulate cortex in the rhesus monkey.

Projections of the basal forebrain magnocellular complex to the limbic telencephalon of the primate were studied by combining double-retrograde tracing with immunocytochemistry. Tracers were injected into anterior cingulate cortex and hippocampus or into hippocampus and amygdala. Retrogradely labeled populations of neurons were topographically arranged but intermingled peripherally. Double-labeled neurons, found only after amygdala-hippocampus injections, were very rare. Approximately 30% of hippocampopetal, 50-70% of amygdalopetal, and 50-90% of cingulopetal neurons were cholinergic; percentages varied among different regions of basal forebrain. These findings further support the concept of a system with a highly organized efferent circuitry.

Amidines↗
PubMed1988

Development of beta 1 and beta 2 adrenergic receptors in baboon brain: an autoradiographic study using [125I]iodocyanopindolol.

[125I]iodocyanopindolol (ICYP) autoradiography was used to investigate the temporal development and distribution of beta 1 and beta 2 receptors in brains of baboons at ages embryonic day 100 (E100), full-term gestation (El80), and 3 years. In all brain regions examined, with the exception of the hippocampus, binding to beta 1 receptors exceeded that to beta 2 receptors. The highest densities of beta 1 receptors were found in the caudate nucleus, putamen, globus pallidus, substantia nigra, and cerebral cortex; intermediate receptor densities were observed in most nuclei of thalamus, and the lowest concentrations were in the hippocampus. At E100, beta receptors were identified in the striatum, globus pallidus, and thalamus. During maturation, the number of beta 1 receptors declined in cortical areas but increased in the head of the caudate and putamen. Significant differences in the developmental distribution of beta receptors during development were also detected: at E100 and E180 beta 1 receptors appeared as patches in the caudate and putamen, but by 3 years of age they were more homogeneously distributed in both regions; changes also occurred in the distribution of binding within cortical layers. Autoradiograms of [125I]ICYP and [3H]mazindol binding show overlapping patches of labeling in the E180 striatum, suggesting a possible developmental association between beta receptors and dopamine high-affinity uptake carrier sites. This study demonstrates that noradrenergic receptors in the primate forebrain undergo significant developmental reorganization with regional variations.

Aging↗