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Biomedical subjects

C B Saper

Publications and source records attributed to C B Saper.

At least 91 records · Page 5Linked to original sources
PubMed1996

Molecular evolution of tau protein: implications for Alzheimer's disease.

The brains of patients with Alzheimer's disease contain deposits of hyperphosphorylated tau proteins that have polymerized into insoluble fibrils. These deposits, in neurofibrillary tangles and dystrophic neurites, correlate with loss of cells and synapses, and consequently with dementia. Neurofibrillary pathology occurs in humans, as well as certain ungulates, including goats, sheep, and cows, but not in nonhuman primates. We hypothesize that the differences among species in the propensity to develop neurofibrillary pathology may be attributable to variations in the amino acid sequence of tau proteins. To investigate this hypothesis, we sequenced tau-encoding mRNA transcripts from the brains of rhesus monkey and domesticated goat and compared them with the known sequences of tau mRNAs from humans. The major difference we observed was that some tau mRNAs from rhesus monkey neocortex contain exon 8, whereas this exon has not been found in cortical tau from human or goat. Cows express very low levels of exon 8, and they tend to develop sparse neurofibrillary pathology with aging. We also found a transcribed tau-related pseudogene in rhesus monkey, which may be present in humans. We propose that differences in the expression of tau and tau-related protein sequences may underlie the predilection of human but not monkey brains to develop neurofibrillary degeneration.

Alzheimer Disease↗
PubMed1996

Inhibition of nitric oxide synthase produces hypothermia and depresses lipopolysaccharide fever.

The labile gas nitric oxide (NO) mediates a wide variety of thermoregulatory processes including vasomotor control, brown fat thermogenesis, and neuroendocrine regulation. Additionally, during endotoxemia, NO modulates the release of cytokines and hypothalamic peptides. To determine the role of NO in thermoregulation and fever, we intravenously injected the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and measured its effects on body temperature during normal thermoregulation and endotoxemia in awake, unrestrained rats. L-NAME produced a stereoselective, dose-dependent hypothermia that lasted up to 4 h after bolus intravenous injection. Intravenous lipopolysaccharide (LPS) produced fever in a dose-dependent manner, which was preceded by hypothermia at higher doses alpha-LPS. NOS inhibition reduced the febrile response to LPS and produced marked hypothermia with a low dose of LPS. These findings indicate that NO may play an important role in thermoregulation and suggest that NO is required for the production of fever.

Animals↗
PubMed1995

Differential distribution of AMPA-selective glutamate receptor subunits in the parabrachial nucleus of the rat.

The parabrachial complex is made up of at least 11 cytoarchitectonically distinct subnuclei which differ in their anatomical connections and neurotransmitter content, as well as the functions they subserve. To determine whether parabrachial subnuclei also express different types of glutamate receptors, we undertook a light microscopic examination of the regional distribution of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor subunits within the parabrachial complex using antibodies directed against synthetic peptides corresponding to the C-terminal parts of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor subunits. Antibodies that recognize GluR1 subunits stained cells mainly in the central lateral parabrachial subnucleus, whereas GluR4 antibodies selectively stained cells in the internal lateral subnucleus. In contrast, antibodies directed against the GLuR2/3 subunits stained neurons in every parabrachial subnucleus, although the most dense labelling was seen in the external lateral cell group. These differences in expression of alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate receptor subtypes may eventually allow selective activation or inhibition of specific subsets of neurons in the parabrachial complex.

Animals↗
PubMed1994

Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration.

Tumor necrosis factor alpha (TNF-alpha) is a cytokine that is responsible, in part, for several aspects of the acute-phase response to inflammation, including the generation of fever. TNF-alpha has direct effects on central nervous system neurons deep within the hypothalamus that are involved in producing the febrile response, but the blood-brain barrier prevents circulating TNF-alpha from having access to these sites. We therefore have hypothesized that TNF-alpha may be produced in the brain and used as a mediator in the cerebral components of the acute-phase response. We used in situ hybridization to determine the distribution of production of TNF-alpha mRNA in the mouse brain after systemic administration of lipopolysaccharide. During the initial phase of fever, hybridization was observed in perivascular cells and neurons in circumventricular organs, including the vascular organ of the lamina terminalis, median eminence, and area postrema, as well as along the ventral surface of the medulla; hybridization was also prominent over many cell in the meninges. During the late phase of the response, hybridization was observed over neurons in the pericircumventricular nuclei such as the anteroventral periventricular and arcuate nuclei of the hypothalamus and the nucleus of the solitary tract. TNF-alpha produced by a cascade of neurons within the brain may participate in the complex autonomic, neuroendocrine, metabolic, and behavioral responses to infection and inflammation.

Acute-Phase Reaction↗
PubMed1994

Neuropeptide-immunoreactive neurons projecting to the paraventricular hypothalamic nucleus in the rat.

The paraventricular nucleus of the hypothalamus (PVH) is innervated by a variety of types of neuropeptide-immunoreactive fibers. The cells of origin for many of these inputs are not known. In the present study, the combined retrograde fluorescence-immunofluorescence method was used to determine the cells of origin for neurotensin-, corticotropin-releasing factor-, brain natriuretic peptide-, somatostatin-, and met-enkephalin-like immunoreactive (-ir) fibers in the PVH. After injections of the fluorescent tracer Fluorogold into the PVH, the pattern of retrograde labeling was as previously reported (Sawchenko and Swanson, 1983, J. Comp. Neurol. 218:121-144; McKellar and Loewy, 1981, Brain Res. 217:351-357). The distribution of each type of double-labeled neuron was unique. Retrogradely labeled enkephalin-ir neurons were concentrated in two locations: the ventral part of the lateral septal nucleus and the lateral anterior nucleus within the AHA. A small cluster of corticotropin-releasing factor-ir neurons in the ventral lateral subnucleus of the bed nucleus of the stria terminalis were retrogradely labeled. Notable concentrations of somatostatin-ir double-labeled neurons were found in the ventral part of the lateral hypothalamic area and the medial part of the arcuate hypothalamic nucleus. Neurotensin-ir double-labeled neurons were most numerous in the anteroventral periventricular nucleus and in the retrochiasmatic area. Many brain natiuretic peptide-ir neurons in the tuberomammillary nucleus of the hypothalamus and in the pedunculopontine and laterodorsal tegmental nuclei were retrogradely labeled. The specificity of these chemically defined projections helps lay the groundwork for examining the functional organization of PVH afferents.

Animals↗
PubMed1994

Cholinergic innervation in the human hippocampal formation including the entorhinal cortex.

The cholinergic innervation of the hippocampal formation is thought to play an important role in memory processes, but its organization in humans has not been described in detail. We studied the cholinergic innervation of the human hippocampal formation by means of immunohistochemistry with polyclonal antisera directed against acetylcholinesterase (AChE), choline acetyltransferase (ChAT), and the low-affinity (p75) nerve growth factor receptor (NGFR). The density of ChAT-like immunoreactive (ChAT-li) fibers differed substantially among the various regions, in general paralleling the pattern of AChE-li staining. One notable exception was the presence of AChE-li cell bodies. In contrast, ChAT immunoreactivity was associated only with fibers and terminals. NGFR-li staining corresponded closely to the ChAT-li fiber pattern. ChAT-li fibers in the CA fields diffusely filled the stratum pyramidale and extended into the stratum oriens and radiatum as well. The highest density was consistently observed in CA4 and CA3 subfields. Staining decreased from CA4 to CA1 and was substantially less dense in the subicular complex. In the entorhinal cortex, the ChAT- and NGFR-li fiber innervation displayed a laminar pattern, most intense over the nests of cells in layer II. There was a trend towards an age-related reduction in the density of ChAT- and AChE-li fibers and terminals. Nonetheless, we also found a surprisingly conserved NGFR-li innervation and the presence of occasional NGFR-li pyramidal cells, providing evidence of a plastic response in the brains of the elderly patients.

Acetylcholinesterase↗
PubMed1994

Neurofibrillary tangles in the cerebral cortex of sheep.

Neurofibrillary degeneration, including neurofibrillary tangles (NFTs) and neuritic plaques, is an important pathological hallmark of Alzheimer's disease (AD). Unfortunately, no practical animal model of neurofibrillary degeneration has been described. We report here the presence of structures in the cerebral cortex of sheep, Ovis aries, that resemble Alzheimer NFTs and neuritic plaques. NFT-like structures and clusters of degenerating neurites are stained by silver impregnation and thioflavin-S, and are immunoreactive with antibodies against tau microtubule-associated proteins. Viewed under the electron microscope, tau-immunoreactive tangles consist of paired helical filaments. Naturally occurring neurofibrillary structures in sheep cortex provide a model for studying the pathobiology of Alzheimer's disease.

Animals↗
PubMed1994

Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat.

The parabrachial complex, also known as the pneumotaxic center or pontine respiratory group, has long been recognized as an important participant in respiratory control. One line of evidence supporting this idea is the demonstration of changes in breathing pattern following injection of neuroactive substances into or near the parabrachial complex. However, it is not yet known exactly which cell groups and projections mediate those responses. In order to address this issue, we explored the topographic organization of respiratory responses to chemical stimulation of the parabrachial complex of the rat and examined the descending projections of the most sensitive sites. Injection of glutamate (5-100 pmol) at specific sites in or near the parabrachial nucleus produced three distinct site-specific response patterns. First, hyperpnea followed glutamate injection into far rostral and midcaudal areas of the Kölliker-Fuse nucleus and most of the lateral parabrachial nucleus, including the external lateral, central lateral, dorsal lateral, and superior lateral subnuclei. Threshold hyperpneic effects were manifested as single, deepened breaths of premature onset. Suprathreshold doses of glutamate at these locations produced tachypnea. Neurons in these sites projected to the ventral respiratory group in the ventrolateral medulla. Second, the most intense inspiratory facilitatory responses were seen at mid to rostral levels of the Kölliker-Fuse nucleus, near the ventrolateral tip of the superior cerebellar peduncle. Even at threshold doses of glutamate, exhalation was incomplete, resulting in a breathing pattern that resembled apneusis (an inspiratory cramp). This site contained an especially dense cluster of neurons that projected either to the ventrolateral medulla or to the dorsal respiratory group in the nucleus of the solitary tract, but not to both areas. The third type of response, decreases in respiratory rate, occurred following glutamate injection at the most lateral and ventral boundaries of the Kölliker-Fuse nucleus. The most sensitive apneic sites were not found in the parabrachial nucleus but along the dorsal and medial edge of the principal sensory trigeminal nucleus and extending ventrally between the sensory and motor trigeminal nuclei. Scattered neurons in these sites were retrogradely labeled from the ventral but not the dorsal respiratory group. These results indicate that there are anatomically and functionally distinct cell populations in and near the parabrachial complex that, when chemically stimulated, can produce specific and sometimes opposing effects on respiration. The predominant effect of lateral parabrachial stimulation is respiratory facilitation, while inhibitory effects are elicited by trigeminal injections of glutamate.

Animals↗
PubMed1993

Distribution and characterization of tumor necrosis factor-alpha-like immunoreactivity in the murine central nervous system.

Tumor necrosis factor-alpha (TNF alpha) is a protein released from macrophages during infection and inflammation. Recent studies suggest that it has several effects within the central nervous system, including generation of fever, enhancement of slow wave sleep, and stimulation of pituitary hormone secretion. We have proposed that TNF alpha may be synthesized by neurons in the CNS and used as a neuromodulator in the pathways involved in the central control of these activities. To test this hypothesis, we have used an antiserum raised against recombinant murine (rm) TNF alpha with an indirect immunoperoxidase technique to stain the murine CNS immunohistochemically. Western blot analysis of mouse brain homogenates revealed one band with electrophoretic mobility identical to that of rmTNF alpha. We identified TNF alpha-like immunoreactive (ir) neurons in the hypothalamus, in the bed nucleus of the stria terminalis, in the caudal raphe nuclei, and along the ventral pontine and medullary surface. TNF alpha ir innervation was widespread within the CNS, particularly in areas involved in autonomic and endocrine regulation, including the hypothalamus, amygdala, bed nucleus of the stria terminalis, parabrachial nucleus, dorsal vagal complex, nucleus ambiguus, and thoracic sympathetic preganglionic cell column. Our data suggest that TNF alpha may serve as a neuromodulator in central pathways involved in the regulation of the autonomic, endocrine and behavioral components of the acute-phase response to inflammation and infection.

Animals↗
PubMed1993

Cholinergic innervation of the human cerebellum.

Cholinergic innervation of the human cerebellum was investigated immunocytochemically by using a polyclonal rabbit antiserum against choline acetyltransferase. Immunoreactive structures were found throughout the cerebellar cortex but were localized predominantly in the vermis, flocculus, and tonsilla. These included 1) a population of Golgi cells in the granular layer; 2) a subpopulation of mossy fibers and glomerular rosettes; 3) thin, varicose fibers closely associated with the Purkinje cell layer and the molecular layer; and 4) a relatively dense network of fibers and terminals contributing to the glomerular formations in the granular layer. In the cerebellar nuclei, some cells stained positively for choline acetyltransferase, and a terminal field pattern could be detected with a distinct but sparse network of varicose fibers. Acetylcholine appears to be a primary transmitter in the vestibulocerebellar pathways at several levels, which may account for the potent effects of muscarinic antagonists in diminishing vestibular vertigo in humans.

Adult↗
PubMed1993

Alz-50 immunohistochemistry in the normal sheep striatum: a light and electron microscope study.

Alz-50 is a monoclonal antibody raised against ventral forebrain tissue from patients with Alzheimer's disease (AD). It was originally believed that the antigen recognized by Alz-50 was only found in degenerating neurons. However, recent studies indicate that Alz-50 stains neurons in a limited but specific distribution in normal brains throughout life. As the antigen recognized by Alz-50 in normal brains may give some insight into the AD degenerative process, we characterized Alz-50 staining in the normal ovine striatum using immunoblots and immunocytochemistry at the light and electron microscope levels. We then compared the Alz-50 staining pattern with those of NADPH diaphorase histochemistry and immunocytochemistry using antisera against several neuropeptides, Alzheimer-related proteins, and heat-shock proteins. Western blot analysis indicated that the epitope recognized by Alz-50 in the normal sheep brain is on the microtubule-associated protein tau, and preadsorbing Alz-50 with a peptide corresponding to the amino terminus of the tau molecule eliminated staining. Alz-50 labeled a single population of cells in the ovine striatum, the medium aspiny neurons. At the light microscope level, the granular staining pattern closely resembled Alz-50 immunoreactive neurons in the normal human striatum and in cells undergoing early degeneration in AD. Alz-50 immunoreactive neurons stained immunocytochemically with antisera against somatostatin, neuropeptide Y, and histochemically for NADPH diaphorase. These cells were morphologically characterized by smooth dendrites, elaborate local axonal plexuses, and indented nuclei with filamentous inclusions. Ultrastructurally, Alz-50 immunodecorated ribosomes and membranous structures (e.g. vesicles, endoplasmic reticulum), and many boutons which contained Alz-50-positive synaptic vesicles. None of the antisera against other Alzheimer-related proteins, including paired helical filament protein, ubiquitin, beta-amyloid protein, or heat-shock proteins specifically stained the population of cells labelled by Alz-50. Other tau antisera also did not specifically stain these cells. We conclude that Alz-50 recognizes an amino terminal epitope that is exposed on tau proteins within a single, discrete population of neurons in the normal sheep striatum. The presence of this epitope in a normal cell population raises the possibility that the early stages of AD degeneration may involve the activation of a normal cellular pathway that modifies the tau molecule.

Alzheimer Disease↗
PubMed1993

The distribution of Alz-50 immunoreactivity in the normal human brain.

Alz-50 is a monoclonal antibody that recognizes normal tau proteins as well as phosphorylated tau proteins that are associated with paired helical filaments in Alzheimer's disease. To establish an accurate baseline for future pathological studies, we examined the distribution of Alz-50 immunoreactivity in normal human brain from infancy to senescence. We found extensive staining patterns of somata and axonal profiles in the striatum, amygdala, hypothalamus, brainstem and spinal cord in all normals at all ages. Similar normal staining patterns were seen in the brains of patients who had suffered trauma, tumors, cerebral infarcts, grade 1 periventricular hemorrhages, and in those who had suffered from amyotrophic lateral sclerosis, Parkinson's disease, multi-systems atrophy and Shy-Drager syndrome. An absence of cell body staining and only minimal axonal staining was noted in the same brains with immunocytochemistry using PHF-1, a monoclonal antibody generated against paired helical filament proteins from Alzheimer brains. The characteristic staining pattern of Alz-50 in normal brains is substantially more extensive than has previously been recognized. This pattern, which presumably describes a specific class of tau proteins, must be distinguished from the pathological staining observed in neurodegenerative diseases.

Aging↗