Neuronal degeneration in human diseases and animal models.
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Animals↗
Biomedical subjects
L J Martin
Publications and source records attributed to L J Martin.
Mesenteric mast cell degranulation in acute T-2 toxin poisoning.
T-2 toxin-induced alterations in rat mesenteric mast cell granulation were measured by cytophotometric analyses of the metachromatic reaction of mast cell granules with azure B. Hypogranulation (diminution of metachromatic material) was observed 8 h following injections of T-2 toxin (0.5-1.5 LD50, i.p.). These data suggest that mast cell activation occurs during acute T-2 intoxication and raise the possibility that mast cell mediators may contribute to toxin-induced cardiovascular collapse.
Animals↗
Cellular localization of a metabotropic glutamate receptor in rat brain.
In rat brain, the cellular localization of a phosphoinositide-linked metabotropic glutamate receptor (mGluR1 alpha) was demonstrated using antibodies that recognize the C-terminus of the receptor. mGluR1 alpha, a 142 kd protein, is enriched within the olfactory bulb, stratum oriens of CA1 and polymorph layer of dentate gyrus in hippocampus, globus pallidus, thalamus, substantia nigra, superior colliculus, and cerebellum. Lower levels of mGluR1 alpha are present within neocortex, striatum, amygdala, hypothalamus, and medulla. Dendrites, spines, and neuronal cell bodies contain mGluR1 alpha. mGluR1 alpha is not detectable in presynaptic terminals. mGluR1 alpha and ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits show differential distributions, but in Purkinje cells, mGluR1 alpha and specific AMPA receptor subunits colocalize. The postsynaptic distribution of mGluR1 alpha is consistent with postulated physiological roles of this subtype of glutamate receptor.
Amino Acid Sequence↗
Biochemical characterization and localization of a non-N-methyl-D-aspartate glutamate receptor in rat brain.
The structure and distribution of non-N-methyl-D-aspartate glutamate receptors in the rat brain were studied using subunit-specific antibodies that recognize the receptor subunit GluR1. The GluR1 protein, a 106-kDa glycoprotein, appears predominantly in synaptic plasma membranes, where it is highly enriched in the postsynaptic densities. When synaptic plasma membranes are solubilized with the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, high-affinity alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) binding and GluR1 immunoreactivity comigrate at a native Mr of 610,000. GluR1 is enriched in the hippocampus and cerebellar cortex but is present throughout the CNS. It is found on neuronal cell bodies and processes within most regions of the brain; within the cerebellum, however, it is localized to the Bergmann glia. These data suggest that the GluR1 protein is a subunit of multimeric AMPA-preferring glutamate receptors present on neurons and on specialized glia.
Animals↗
The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely distributed at synapses in rat brain.
The beta-adrenergic receptor kinase (beta ARK) phosphorylates the agonist-occupied beta-adrenergic receptor to promote rapid receptor uncoupling from Gs, thereby attenuating adenylyl cyclase activity. Beta ARK-mediated receptor desensitization may reflect a general molecular mechanism operative on many G-protein-coupled receptor systems and, particularly, synaptic neurotransmitter receptors. Two distinct cDNAs encoding beta ARK isozymes were isolated from rat brain and sequenced. The regional and cellular distributions of these two gene products, termed beta ARK1 and beta ARK2, were determined in brain by in situ hybridization and by immunohistochemistry at the light and electron microscopic levels. The beta ARK isozymes were found to be expressed primarily in neurons distributed throughout the CNS. Ultrastructurally, beta ARK1 and beta ARK2 immunoreactivities were present both in association with postsynaptic densities and, presynaptically, with axon terminals. The beta ARK isozymes have a regional and subcellular distribution consistent with a general role in the desensitization of synaptic receptors.
Amino Acid Sequence↗
Alzheimer's disease-type brain abnormalities in animal models.
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Alzheimer Disease↗
Amyloidosis in aging and Alzheimer's disease.
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Aged↗
Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis.
Renewed interest in the antihistamine action of ascorbic acid has emerged with the recently recognized immunosuppressive role of histamine. We examined the antihistamine effect of acute and chronic vitamin C (VC) administration and its effect on neutrophil chemotaxis in healthy men and women. In the chronic study, 10 subjects ingested a placebo during weeks 1, 2, 5 and 6, and 2 g/day of VC during weeks 3 and 4. Fasting blood samples were collected after the initial 2-week period (baseline) and at the end of weeks 4 and 6. Plasma ascorbate rose significantly following VC administration compared to baseline and withdrawal values. Neutrophil chemotaxis rose 19% (NS) during VC administration, and fell 30% after VC withdrawal, but these changes were not correlated to plasma ascorbate levels (r = 0.01). Chemotaxis was inversely correlated to blood histamine (r = -0.32, p = 0.045), and, compared to baseline and withdrawal values, histamine levels were depressed 38% following VC supplementation. Blood histamine and neutrophil chemotaxis did not change 4 hours following a single 2 g dose of ascorbic acid, although plasma ascorbate rose 150%. These data indicate that VC may indirectly enhance chemotaxis by detoxifying histamine in vivo.
Adult↗
The bed nucleus-amygdala continuum in human and monkey.
The cytoarchitecture and distributions of seven neuropeptides were examined in the the bed nucleus of the stria terminalis (BST), substantia innominata (SI), and central and medial nuclei of the amygdala of human and monkey to determine whether neurons of these regions form an anatomical continuum in primate brain. The BST and centromedial amygdala have common cyto- and chemo-architectonic characteristics, and these regions are components of a distinct neuronal complex. This neuronal continuum extends dorsally, with the stria terminalis, from the BST and merges with the amygdala; it extends ventrally from the BST through the SI to the centromedial amygdala. The cytoarchitectonics of the BST-amygdala complex are heterogeneous and compartmental. The BST is parcellated broadly into anterior, lateral, medial, ventral, supracapsular, and sublenticular divisions. The central and medial nuclei of the amygdala are also parcellated into several subdivisions. Neurons of central and medial nuclei of the amygdala are similar to neurons in the lateral and medial divisions of the BST, respectively. Neurons in the SI form cellular bridges between the BST and amygdala. The BST, SI, and amygdala share several neuropeptide transmitters, and patterns of peptide immunoreactivity parallel cytological findings. Specific chemoarchitectonic zones were delineated by perikaryal, peridendritic/perisomatic, axonal, and terminal immunoreactivities. The results of this investigation demonstrate that there is a neuronal continuity between the BST and amygdala and that the BST-amygdala complex is prominent and discretely compartmental in forebrains of human and monkey.
Amygdala↗
Amyloid precursor protein in aged nonhuman primates.
In individuals with Alzheimer disease and in aged nonhuman primates, deposits of amyloid occur in senile plaques in brain parenchyma and in the walls of some meningeal and cortical vessels. Amyloid is primarily composed of beta/A4, a 4-kDa peptide derived from the transmembrane form of an amyloid precursor protein (APP). We examined the distribution of beta/A4 and APP (outside the beta/A4 domain) in cerebral cortices of monkeys ranging in age from 4 to 41 years. In all animals, APP immunoreactivity was present in cell bodies, proximal dendrites, and axons of cortical neurons. In aged animals, all of which showed senile plaques, large APP-positive axons were conspicuous, and APP immunoreactivity was present in neurites around beta/A4-immunoreactive plaques. In some plaques, APP-immunoreactive elements were located in proximity to deposits of beta/A4. The presence of APP immunoreactivity in neuronal perikarya, dendrites, axons, and in neurites within beta/A4-containing plaques supports the hypothesis that neurons can serve as one source of amyloid deposited in brain parenchyma.
Aging↗
Effect of 4,7,10,13,16,19-docosahexaenoic acid on triglyceride accumulation and secretion in rat hepatocytes in culture.
We have investigated the effect of oleic (18:1) and 4,7,10,13,16,19-docosahexaenoic (22:6 omega 3) acids on triglyceride (TG) accumulation, secretion and reuptake in rat hepatocytes in culture. We also calculated the percentage of total TG, TG-esterified 18:1 and TG-esterified 22:6 omega 3 that were secreted relative to the total accumulation (intra + extracellular TG). Both fatty acids were incorporated mainly in the intracellular TG fraction. Treatment with 18:1 but not with 22:6 omega 3 increased the quantity of TG secreted into the culture medium relative to controls. Treatment with 22:6 omega 3 caused a greater accumulation of intracellular TG than 18:1. This arises in part from the preferential retention of 22:6 omega 3-enriched TG by the hepatocytes. At 24 hr, there was no longer any difference in the net secretion of TG by 18:1 and 22:6 omega 3-treated cells, which may be a consequence of the reuptake of TG-esterified 18:1. There was no reuptake of TG-esterified 22:6 omega 3. We conclude that inhibition of hepatocyte TG synthesis is not obligatory for 22:6 omega 3-induced diminution of TG secretion.
Animals↗
The striatal mosaic in primates: patterns of neuropeptide immunoreactivity differentiate the ventral striatum from the dorsal striatum.
Patterns of immunoreactivity for calcium-binding protein, tyrosine hydroxylase and four neuropeptides in the ventral striatum (nucleus accumbens, olfactory tubercle and ventromedial parts of the caudate nucleus and putamen) were compared to patterns of these markers in the dorsal striatum (the majority of the neostriatum) in rhesus monkey. The striatal mosaic was delineated by calcium-binding protein and tyrosine hydroxylase immunoreactivities. Both markers were found preferentially in the matrix of the dorsal striatum. The mosaic configurations of tyrosine hydroxylase, but not calcium-binding protein immunoreactivity, were similar in dorsal and ventral striatal regions. Substance P and leucine-enkephalin were not distributed homogeneously; distinct types and the prevalence of patches of substance P and leucine-enkephalin immunoreactivity distinguish the dorsal striatum from the ventral striatum and distinguish the caudate nucleus from the putamen. In the dorsal striatum, substance P and leucine-enkephalin patches consist of dense islands of immunoreactive neurons and puncta or clusters of immunoreactive neurons marginated by a dense rim of terminal-like puncta; the matrix was also enriched in leucine-enkephalin-immunoreactive neurons but contained less substance P-immunoreactive neurons. Patches were more prominent in the caudate nucleus than in the putamen. In the caudate, compartments low in tyrosine hydroxylase and calcium-binding protein immunoreactivities corresponded to cytologically identified cell islands and to patches enriched in substance P and leucine-enkephalin. These patches had a discrete infrastructure based on the location of substance P and leucine-enkephalin-immunoreactive neurons and terminals. In the ventral striatum, patches that showed low levels of substance P and leucine-enkephalin immunoreactivities were embedded in a matrix rich in immunoreactive cell bodies, fibers and terminals. In the accumbens, regions showing little tyrosine hydroxylase were in spatial register with patches low in substance P and leucine-enkephalin. Neurotensin- and somatostatin-immunoreactive neurons or processes were also compartmentally organized, particularly in the ventral striatum. Neurotensin-immunoreactive neurons were present predominantly in the nucleus accumbens but not in the dorsal striatum. Some regions enriched in neurotensin immunoreactivity were spatially registered with zones low in tyrosine hydroxylase, substance P and zones enriched in leucine-enkephalin. Areas enriched in somatostatin-immunoreactive processes overlapped with both tyrosine hydroxylase-rich and -poor regions in the ventral striatum. Our results show that the chemoarchitectonic topography of the striatal mosaic is different in the dorsal and ventral striatum of rhesus monkey and that the compartmental organization of some neurotransmitters/neuropeptides in the ventral striatum is variable and not as easily divisible into conventional patch and matrix regions as in the dorsal striatum.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
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↗
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↗
Social deprivation of infant rhesus monkeys alters the chemoarchitecture of the brain: I. Subcortical regions.
Rhesus monkeys (Macaca mulatta) reared during the first year of life without social contact develop persistent stereotyped movements, self-directed behaviors, and psychosocial abnormalities, but neurobiological mechanisms underlying the behaviors of socially deprived (SD) monkeys are unknown. Monkeys were reared in total social deprivation for the first 9 months of life; control monkeys were reared socially (SR) with mothers and peers. Subjects were killed at 19-24 yr of age. Because the behaviors of SD monkeys are reminiscent of changes in striatal or amygdalar function, we used immunocytochemistry for substance P (SP), leucine-enkephalin (LENK), somatostatin, calbindin, and tyrosine hydroxylase (TH) to evaluate qualitatively and quantitatively patterns of neurotransmitter marker immunoreactivity within subcortical regions. In SD monkeys, the chemoarchitecture of the striatum was altered. Neuronal cell bodies and processes immunoreactive for SP and LENK were depleted markedly in patch (striosome) and matrix regions of the caudate nucleus and putamen; the average density of SP-immunoreactive neurons was reduced 58% relative to SR monkeys. Calbindin and TH immunoreactivities were diminished in the matrix of caudate and putamen of SD monkeys. TH-immunoreactive neurons, but not cresyl violet-stained neurons, in the substantia nigra pars compacta were decreased (43%) in SD monkeys. Peptide-immunoreactive terminals were reduced in the globus pallidus and substantia nigra in SD monkeys. The nucleus accumbens was the least affected of striatal regions. Striatal somatostatin immunoreactivity wa qualitatively and quantitatively similar in SD and SR monkeys. Several regions, for example, bed nucleus of the stria terminalis, amygdala, and basal forebrain magnocellular complex, that were in the same sections and are enriched in these markers did not appear altered in SD monkeys, suggesting a regional specificity for vulnerability. The altered chemoarchitecture of some basal ganglia regions in adult monkeys that experienced social deprivation as infants suggests that the postnatal maturation of neurotransmitter phenotypes in some structures is influenced by social environment. Abnormal motor and psychosocial behaviors resulting from this form of social/sensory deprivation may result from alterations in peptidergic and dopaminergic systems within the basal ganglia.
Amygdala↗
The human pineal gland in aging and Alzheimer's disease: patterns of cytoskeletal antigen immunoreactivity.
Patients with Alzheimer's disease (AD) and some aged controls may have diminished functions of the pineal gland. In this immunocytochemical study, we stained pineal glands from cases of AD and young and aged controls for cytoskeletal elements and amyloid. We found no evidence of neurofibrillary tangles (NFT) or the accumulation of neurofilaments, tau, A68, or beta/A4 amyloid deposition in pinealocytes or associated structures in cases of AD or controls. In both AD and controls, we observed dense immunoreactivity for phosphorylated neurofilaments in marginal plexuses associated with processes of pinealocytes, boutons, and knob-like endings. The accumulation of phosphorylated neurofilaments in the processes of pinealocytes appears to be a normal morphological characteristic of the pineal gland and may not represent a pathological change.
Adolescent↗
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↗
Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport.
In the brains of aged humans and cases of Alzheimer disease, deposits of amyloid in senile plaques are located in proximity to nerve processes. The principal component of this extracellular amyloid is beta/A4, a peptide derived from a larger amyloid precursor protein (APP), which is actively expressed in brain and systemic organs. Mechanisms that result in the proteolysis of APP to form beta/A4, previously termed beta-amyloid protein, and the subsequent deposition of the peptide in brain are unknown. If beta/A4 in senile plaques is derived from neuronally synthesized APP and deposited at locations remote from sites of synthesis, then APP must be transported from neuronal cell bodies to distal nerve processes in proximity to deposits of amyloid. In this study, using several immunodetection methods, we demonstrate that APP is transported axonally in neurons of the rat peripheral nervous system. Moreover, our investigations show that APP is transported by means of the fast anterograde component. These findings are consistent with the hypothesis of a neuronal origin of beta/A4, in which amyloid is deposited in the brain parenchyma of aged individuals and cases of Alzheimer disease. In this setting, we suggest that APP is synthesized in neurons and delivered to dystrophic nerve endings, where subsequent alterations of local processing of APP result in deposits of brain amyloid.
Acetylcholinesterase↗