Search Results - (Author, Cooperation:R. Nitsch)

2014-02-21

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Adaptor Proteins, Signal Transducing/deficiency/genetics/*metabolism ; Animals ; Anticoagulants/pharmacology/therapeutic use ; Female ; Killer Cells, Natural/drug effects/*immunology/metabolism ; Male ; Mammary Neoplasms, Experimental/drug therapy/genetics/immunology/*pathology ; Melanoma, Experimental/drug therapy/genetics/immunology/*pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasm Metastasis/drug therapy/*immunology/prevention & control ; Proto-Oncogene Proteins/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins c-cbl/deficiency/genetics/*metabolism ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/*metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; Ubiquitination ; Warfarin/pharmacology/therapeutic use

0304-8853

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Physics

Electronic Resource

1749-6632

Blackwell Publishing Journal Backfiles 1879-2005

Natural Sciences in General

The role of brain amyloid in the pathogenesis of Alzheimer's disease (AD) is discussed controversially, but combined genetic and biochemical evidence points to a central role of the gene encoding the amyloid precursor APP in at least some forms of AD. This article proposes that preventing brain amyloid formation is a rational concept for drug treatment of AD. We suggest that pharmacologically active ligands for specific cell surface receptor subtypes—normally stimulated by neurotransmitters, growth factors, and cytokines—constitute a class of chemicals that might be useful to accelerate processing of APP into non-amyloidogenic, and biologically active, derivatives. This class of agents includes muscarinic m1 and m3 agonists, serotoninergic 5-HT2a and 5-HT2c agonists, glutamatergic mGluR1 agonists, as well as agonists for bradykinin and vasopressin receptors.

Electronic Resource

1435-1463

Dementia of Alzeimer type ; amino acids ; neurotoxic effect ; neuronal damage ; insulin receptor

Springer Online Journal Archives 1860-2000

Medicine

Summary A massive cerebral release of amino acids and ammonia was found in early-onset dementia of Alzheimer type. Aspartate and glycine were liberated in high concentrations, whereas glutamate remained rather unchanged. This excess cerebral protein catabolism is due to a 44% reduction in cerebral glucose metabolism. Whereas glutamate and other glucoplastic amino acids may substitute glucose, elevated aspartate may contribute to neuronal damage. The results are discussed with respect to a possible neuronal insulin/insulin receptor deficiency.

Electronic Resource

1432-0568

Key words Neurodegeneration ; Entorhinal cortex ; Hippocampus ; Immunocytochemistry

Springer Online Journal Archives 1860-2000

Medicine

Abstract  The transentorhinal cortex (TEC) is a primate-specific transition zone between the entorhinal allocortex and the temporal isocortex. Neurons in the lamina pre-alpha of TEC are known to be the first to develop intraneuronal changes in the course of Alzheimer’s disease. In order to shed light on this important feature, we studied as yet unknown morphological and neurochemical characteristics of the TEC of the African green monkey (Cercopithecus aethiops sabaeus). Using light- and electron-microscopic immunocytochemistry, the distribution and morphology of neurons containing calcium-binding proteins were described and compared with those in the adjacent cortices. Light-microscopic analysis revealed that parvalbumin-containing neurons were distributed in all cortical layers. Calbindin-containing cells were fewer but also present in each layer. Calretinin-containing neurons were largely confined to the upper layers of the TEC. All three types of neuron showed pyramidal-like, multipolar and bipolar shapes; their dendrites were smooth or beaded. Ultrastructural studies revealed immunopositive somata with infolded nuclei and large amounts of cytoplasm. The somata were only sparsely innervated by symmetric synapses. Immunopositive dendrites were almost exclusively covered with immunonegative axon terminals establishing symmetric and asymmetric synapses. Immunopositive terminals established symmetric contacts with immunonegative dendrites and somata. Only occasionally, could synaptic contacts between immunopositive pre- and postsynaptic structures be observed. The comparison of neurons in the TEC and adjacent cortices revealed no striking differences. In summary, the morphological and neurochemical characteristics of TEC neurons as analyzed in our study do not provide an explanation for the early onset of neurodegenerative changes in the TEC.

Electronic Resource

1432-119X

Springer Online Journal Archives 1860-2000

Biology

Medicine

Summary Perfusion-fixed tissue blocks were incubated in high molar sucrose solutions, shock frozen in melting isopentane, and sectioned on a conventional cryostat. Semithin sections (2–4 μm) alternatingly stained for parvalbumin and glutamate decarboxylase enabled us to demonstrate the coexistence of both antigens in the same cell. Thick sections (40 μm) of central and peripheral nervous system tissue were immunostained and processed for correlated light and electron microscopic studies. At the electron microscopic level, the preservation of ultrastructural features such as membranes and synaptic contacts was comparable to that normally seen in vibratome sectioned material. Hence, this technique can successfully be used for preembedding coexistence studies and electron microscopic preembedding immunocytochemistry when vibratome sectioning is problematic.

Electronic Resource

1432-1106

Key words Hippocampus ; Commissural fibers ; Reactive sprouting ; Synaptogenesis ; Synaptophysin ; Rat

Springer Online Journal Archives 1860-2000

Medicine

Abstract  Expression of the synaptic vesicle protein synaptophysin was studied in lesion-induced sprouting neurons of the contralateral entorhinal cortex and in the contralateral dentate gyrus using immunocytochemistry at the light- and electron-microscopic level. Perikaryal immunoreactivity for synaptophysin was found between 8 and 10 days postlesion. Light microscopy revealed that synaptophysin immunostaining was present in almost all neurons of layers II and III of the contralateral medial entorhinal cortex. These neurons give rise to the sprouting, crossed temporodentate pathway. In addition, some hilar neurons of the contralateral dentate gyrus, which are the parent cells of sprouting commissural fibers, were immunostained for synaptophysin. Transient immunostaining for synaptophysin was observed within cell bodies and dendrites. Additionally, the cell bodies were outlined by immunoreactive puncta, identified by electron microscopy as nerve terminals. Our results revealed that sprouting neurons express the major synaptic vesicle protein synaptophysin during reactive synaptogenesis in a pattern that reflects biosynthesis and sorting of this protein as seen in developing neurons during synapse formation.

Electronic Resource

1432-0878

Key words: Phaseolus vulgaris leucoagglutinin ; Anterograde tracing ; Entorhinal cortex ; Crossed temporo-ammonic pathway ; Crossed temporo-dentate pathway ; Rat (Sprague Dawley)

Springer Online Journal Archives 1860-2000

Biology

Medicine

Abstract. Neurons of the entorhinal cortex project to the hippocampus proper and dentate gyrus. This projection is called the ”perforant pathway” because it perforates the subiculum; current usage applies this term to all entorhino-hippocampal fibers. However, entorhinal fibers also reach Ammon’s horn via the alveus (”alvear pathway”), an alternative route first described by Cajal. The anterograde tracer Phaseolus vulgaris leucoagglutinin (PHAL) was used in order to analyze the contribution of this pathway to the temporo-ammonic projection. In the temporal portion of the rat hippocampus, most of the entorhinal fibers reach Ammon’s horn after perforating the subiculum (classical perforant pathway). At more septal levels, the number of entorhinal fibers that take the alvear pathway increases; in the septal portion of the hippocampal formation, most of the entorhinal fibers to hippocampal subfield CA1 reach this subfield via the alveus. These fibers make sharp right-angle turns in the alveus, perforate the pyramidal cell layer, and finally terminate in the stratum lacunosum-moleculare. The crossed temporo-ammonic fibers reach their termination area in the stratum lacunosum-moleculare of CA1 almost exclusively via the alveus. These data indicate that the alveus is a major route by which entorhinal fibers reach their targets in CA1.

Electronic Resource

1435-1463

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

1435-1463

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

1435-1463

Keywords: Brain lipid metabolism ; free fatty acids ; phospholipids ; streptozotocin ; neurodegeneration ; animal model.

Springer Online Journal Archives 1860-2000

Medicine

Summary. Streptozotocin (STZ) is a diabetogenic drug that disrupts glucose and energy metabolism in brain. To study its effect on brain lipids, tissue concentrations of free fatty acids and phospholipids were measured in the temporal cortex and the hippocampus of adult rats 3 weeks after a single intracerebroventricular (icv) injection of STZ. STZ increased concentrations of palmitic acid and stearic acid in temporal cortex and these of arachidonic acid both in the anterior part of the hippocampus and in CA1. In addition, palmitic acid and stearic acid concentrations were elevated in the anterior hippocampus. In contrast, STZ decreased brain cortex levels of phosphatidylethanolamine and phosphatidylserine. These data show that STZ alters brain lipid metabolism. They suggest that oxidative phospholipid breakdown is accelerated by STZ. These changes may be related to decreased brain glucose utilization and energy formation.

Electronic Resource

1435-1463

Keywords: Dementia ; biochemical markers ; heavy metals ; neurodegeneration.

Springer Online Journal Archives 1860-2000

Medicine

Summary. Alzheimer's disease (AD) is a common neurodegenerative disorder that leads to dementia and death. In addition to several genetic parameters, various environmental factors may influence the risk of getting AD. In order to test whether blood levels of the heavy metal mercury are increased in AD, we measured blood mercury concentrations in AD patients (n = 33), and compared them to age-matched control patients with major depression (MD) (n = 45), as well as to an additional control group of patients with various non-psychiatric disorders (n = 65). Blood mercury levels were more than two-fold higher in AD patients as compared to both control groups (p = 0.0005, and p = 0.0000, respectively). In early onset AD patients (n = 13), blood mercury levels were almost three-fold higher as compared to controls (p = 0.0002, and p = 0.0000, respectively). These increases were unrelated to the patients' dental status. Linear regression analysis of blood mercury concentrations and CSF levels of amyloid β-peptide (Aβ) revealed a significant correlation of these measures in AD patients (n = 15, r = 0.7440, p = 0.0015, Pearson type of correlation). These results demonstrate elevated blood levels of mercury in AD, and they suggest that this increase of mercury levels is associated with high CSF levels of Aβ, whereas tau levels were unrelated. Possible explanations of increased blood mercury levels in AD include yet unidentified environmental sources or release from brain tissue with the advance in neuronal death.

Electronic Resource

1435-1463

Keywords: Alzheimer's disease ; amyloid ; muscarinic receptors ; acetylcholine ; brain slices.

Springer Online Journal Archives 1860-2000

Medicine

Summary. To examine the effects of the combined muscarinic m1-agonist/m2-antagonist Lu 25-109 on regulated processing of the amyloid protein precursor (APP), we used both transfected cells expressing human muscarinic m1 or m2 acetylcholine receptors, and fresh rat hippocampal slices. Lu 25-109 readily stimulated APPs secretion from HEK 293 cells overexpressing m1, but not m2, receptors, as well as from the hippocampal brain slices. Time-course analyses revealed a rapid (5–35 minutes), and a delayed (55–75 minutes) secretory response to Lu 25-109 with distinct concentration profiles suggesting two distinct cell biological mechanisms. Both responses appeared to reflect post-translational mechanisms because levels of APP message were unchanged after 60 minutes of stimulation with Lu 25-109. In comparison to carbachol, Lu 25-109 had a significantly lower intrinsic activity at muscarinic m1 receptors, compatible with a pharmacological profile as a partial agonist at recombinantly expressed m1 receptors. In as much as stimulation of APPs secretion is associated with reduced formation of Aβ peptides, Lu 25-109 may be useful to reduce Aβ generation, and thus, slow amyloid plaque formation. Moreover, Lu 25-109 may be useful in promoting the known neurotrophic and neuroprotective biological functions of secreted APPs.

Electronic Resource

1435-1463

Glucose utilization ; dementia of Alzheimer type ; late-onset ; brain insulin ; insulin receptor

Springer Online Journal Archives 1860-2000

Medicine

Summary Global cerebral blood flow and the cerebral metabolic rates of oxygen, CO2, glucose and lactate were studied in 11 patients aged 61–78 years who had been clinically diagnosed as suffering from incipient late-onset dementia of the Alzheimer type (DAT), and in 7 patients aged 66–83 years, in whom advanced late-onset DAT had been diagnosed, using the Kety-Schmidt technique. In incipient late-onset DAT, the predominant abnormality was a 45% reduction in cerebral glucose utilization, whereas cerebral blood flow and the cerebral metabolic rate of oxygen were diminished by only 17% and 18%, respectively. A severe imbalance between oxygen utilization and glucose utilization thus became obvious. In contrast, in advanced stages of late-onset DAT, this imbalance between oxygen and glucose utilization rates in the brain became smaller and smaller, and cerebral blood flow diminished markedly; these biological brain parameters finally all settled down at between 55% and 65% of the corresponding control values. The predominant abnormality in brain glucose utilization in incipient late-onset DAT may be associated with an impairment of its control mechanism(s), which are assumed to be either an influence of brain insulin action, or brain insulin receptor function, or both.

Electronic Resource