Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0752347 (Dementia with Lewy bodies)
 1,653 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify axonal guidance mechanisms involved in pathway formation by spinal interneurons, the pattern of axonal outgrowth was examined following three kinds of perturbations: (1) rotation of three segments of the neural tube around the dorsal-ventral axis by 90 degrees or 180 degrees (D-V rotation), (2) rotation of three segments of the neural tube around the rostral-caudal axis (R-C rotation), and (3) transplantation of brainstem into thoracic spinal segments (BS transplantation). Following D-V rotation, it was observed that circumferential axons near the junction between rotated graft (RG) and host cord changed their course so as to project toward the ectopic floor plate. This supports the notion that the floor plate exerts a chemotropic-like effect on the directional projection of circumferential axons. The longitudinal fibers in the ventral funiculus (VF) were able to grow through the transplant junction when the VF was well apposed to the VF of the RG. However, in most cases, the longitudinal fibers in the VF that were not apposed to the VF of the RG made a medial turn at the junction. After turning, some of them made a U-turn into the contralateral VF, whereas others grew circumferentially around the junction zone, then exited the spinal cord; still others directly entered the RG. The majority of fibers that entered the RG were located in the VF, though a small number of such fibers were also located in both the lateral and dorsal funiculus (LF and DF, respectively). The fibers that entered the LF shifted ventrally, whereas the fibers in the DF remained within the DF. These results suggest that there may be some matching mechanism between specific fibers and the funiculus through which the fibers normally project. Moreover, there may be a barrier between the LF and the DF that prevents the fibers in the DF from shifting ventrally. In R-C rotation experiments, the projection of axons of dorsolateral border cells (DLB-cells), which are known to give rise almost exclusively to commissural ascending axons, was examined. Following the injection of HRP into the rostral junctional region, retrogradely labeled DLB-cells were observed in the rotated segments only on the side contralateral to the injection. Labeled DLB-cells were also observed in the segments caudal to the rotated segments. These results suggest that putative rostrocaudal directional cues that guide the axons of DLB-cells may arise from outside of the segments in which the decision to turn is made.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:An experimental analysis of in vivo guidance cues used by axons of spinal interneurons in the chick embryo: evidence for chemotropism and related guidance mechanisms. 165 78

GAP-43 is a growth-associated phosphoprotein expressed at high levels in neurons during development, axonal regeneration, and neuritic sprouting. GAP-43 gene expression in mature neurons is probably functionally important for the structural remodeling of synapses as required for learning and establishing new memory. The widespread aberrant neuritic growth accompanied by impaired synaptic plasticity in Alzheimer's disease (AD) suggests that abnormal GAP-43 gene expression may contribute to the cascade of neurodegeneration. In the present study, end-stage AD brains exhibited reduced neuronal expression but increased glial cell levels of GAP-43 mRNA and protein. Glial cell localization of GAP-43 gene expression was confirmed by in situ hybridization of cerebral tissue, Northern blot analysis of microdissected cerebral white matter, and independent analysis of astrocytoma cell lines and primary malignant astrocytomas. In addition, in AD, GAP-43 immunoreactivity was translocated from the cytosol to membranes of swollen neuritic (dendritic) and glial cell processes throughout cerebral cortex and white matter. Downregulated and aberrant neuronal GAP-43 gene expression appears to reflect an important molecular lesion that precedes and progresses with the widespread synaptic disconnection and dementia in AD. At the same time, the presence of similar neuronal abnormalities in Pick's disease, diffuse Lewy body disease, Parkinson's disease, and Down syndrome suggests common mechanisms in the respective cascades of neurodegeneration. Finally, the finding of aberrantly increased glial cell GAP-43 gene expression in AD exposes a previously unrecognized neurodegenerative change that may account for the axonal loss and white matter atrophy detected early in the course of disease.
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PMID:Aberrant GAP-43 gene expression in Alzheimer's disease. 757 69

Dementia associated with cortical and subcortical Lewy bodies (LB's) is a distinct entity with variable clinico-pathological presentation. We present the case of a 49-year-old male with progressive dementia. At autopsy, the brain showed diffuse cortical atrophy and ubiquitin-positive LB's in the dentate gyrus, deep layers of the neocortex, basal ganglia, nucleus basalis and substantia nigra. Thioflavine S stains of the neocortex and hippocampus were negative for the presence of plaques and tangles. Anti-ubiquitin immunostaining revealed abundant dystrophic neurites, torpedo-like axons and abnormal neuritic processes in the molecular layer of the dentate gyrus, pyramidal cell layer in CA1, subiculum, deep layers of the neocortex, claustrum, caudate, putamen and globus pallidus. Relatively mild neuritic alterations were observed in the nucleus basalis of Meynert (NbM) and locus ceruleus. The presence of this unique type of axonal damage associated with Lewy body disease, in the absence of plaques and tangles, might suggest a divergent mechanism of neuritic injury in the wide spectrum of this disorder.
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PMID:Atypical diffuse Lewy body disease with neuritic abnormalities. 828 26

Senile dementia of Lewy body type or Lewy body dementia (LBD), characterized neuropathologically by the presence of Lewy bodies in the brainstem and cortex, and in most cases neocortical senile plaques (but few or no tangles), bears a closer resemblance to Parkinson's (PD) than to Alzheimer disease (AD) in its cholinergic neurochemical pathology. Thus, reductions in the biochemical activity of choline acetyltransferase were generally more extensive in neo- as opposed to archicortical regions in LBD (especially hallucinating cases) and in PD, whereas muscarinic receptor binding was significantly increased in LBD and PD but not in AD. Nerve growth factor receptor (P75) assessed immunocytochemically in the archicortex were decreased in PD and, to a lesser extent, in LBD in conjunction with reductions of neuronal numbers in the nucleus of Meynert (Ch4), but were relatively spared in AD. These observations indicate that although AD is primarily associated with dysfunction of cholinergic axonal input to the cortex, LBD and PD are more likely to involve degeneration of the basal forebrain cholinergic system. Relevance of the findings in terms of aetiopathology and cholinergic treatment strategies is discussed.
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PMID:Cholinergic transmitter and neurotrophic activities in Lewy body dementia: similarity to Parkinson's and distinction from Alzheimer disease. 834 30

In susceptible species, aluminum induces cytoskeletal changes in which neurofilaments accumulate in neuronal cell bodies and proximal axonal enlargements. To determine if microtubule-associated proteins (MAPs) are altered in this model, we examined the spinal cords of aluminum- and saline-treated control rabbits at several time points after treatment. Transient decreases in tau and MAP2 immunoreactivity in neurons in aluminum-intoxicated rabbits were demonstrated with immunocytochemistry. An antibody directed against Alzheimer's disease paired helical filaments labeled neurons in aluminum-treated rabbits but not controls. MAP5 immunoreactivity in the cell body cytoplasm was displaced by aluminum-induced tangles. The transient decreases in MAP2 and tau immunoreactivity did not reflect alterations in protein levels measured using immunoblotting. The transient antigenic changes in tau and MAP2 may reflect conformational changes in these cytoskeletal proteins. Aluminum-induced pathology provides a model for studying perturbations in MAPs and neurofilament proteins that are characteristic of many human neurodegenerative diseases such as Alzheimer's disease, diffuse Lewy body disease, Parkinson's disease, and amyotrophic lateral sclerosis.
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PMID:Aluminum-induced neuropathology: transient changes in microtubule-associated proteins. 894 45

Aluminum is a neurotoxin and in susceptible species induces a neurofibrillary pathology characterized by argentophilic masses in neuronal perikarya and in axonal spheroids. These inclusions are known to contain neurofilament proteins. Using immunocytochemistry and immunoblotting, we demonstrate that tau is a component of these aluminum-induced neurofibrillary tangles (Al-NFTs) in rabbits. Double-label immunocytochemistry experiments reveal co-localization of phosphorylated neurofilaments (using SMI31) and tau (using tau-1, tau-5, AT8, and PHF-1) in the perikaryal Al-NFTs. Non-phosphorylated tau (detected using tau-1) occupies a smaller area of the Al-NFT than the total pool of tau proteins (detected using tau-5). The area of total tau and non-phosphorylated tau immunolabeling in the Al-NFT increases as the size of the Al-NFT (i.e., the proportion of cell area occupied by the Al-NFT) increases. The proportion of cell area (outside of the Al-NFT) occupied by tau (as indicated by tau-5) decreases as the area of tau in the Al-NFT increases and as the size of the Al-NFT in the cell increases. Immunoblotting experiments demonstrate 1) the specificity of the tau antibody labeling and verify a lack of cross-reactivity of the tau-5 antibody to neurofilament proteins in rabbit tissue; and 2) no alterations in the levels of tau resulting from aluminum-treatment. These data suggest that as the size of the Al-NFT in a cell increases there is less tau in the neuronal perikarya. Therefore, there may be less tau in the perikarya available to perform normal functions such as microtubule polymerization and stabilization. Tau and neurofilament proteins are perturbed in a number of neurodegenerative disorders such as Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease. Aluminum-induced neurofibrillary pathology may provide a model to study perturbation in tau and neurofilaments, their phosphorylation and deposition into pathological inclusions.
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PMID:Tau in aluminum-induced neurofibrillary tangles. 921 89

We investigated the hippocampal pathology in diffuse Lewy body disease (DLBD) using alpha-synuclein immunohistochemistry. Ubiquitin-positive intrahippocampal structures caused by the degeneration of terminal axons of the perforant pathway were observed to be alpha-synuclein immunoreactive. These alpha-synuclein-positive degenerative terminals contained granulo-filamentous or vesiculo-tubular components similar to those of Lewy bodies (LB) immunoelectron microscopically, suggesting that alpha-synuclein may abnormally aggregate into filamentous or membranous cytoskeletal components including neurofilaments and synaptic vesicles in DLBD. A 'dying back' degenerating process due to a blockage of axonal transport may explain why the degenerative terminals and LB share similar alpha-synuclein-positive components, but the origin cells of the perforant pathway contain only a few LB.
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PMID:Degenerative terminals of the perforant pathway are human alpha-synuclein-immunoreactive in the hippocampus of patients with diffuse Lewy body disease. 987 32

The presynaptic protein alpha-synuclein is a prime suspect for contributing to Lewy pathology and clinical aspects of diseases, including Parkinson's disease, dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. alpha-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense mutations (A53T and A30P) in the alpha-synuclein gene are genetically linked to rare familial forms of Parkinson's disease. Under control of mouse Thy1 regulatory sequences, expression of A53T mutant human alpha-synuclein in the nervous system of transgenic mice generated animals with neuronal alpha-synucleinopathy, features strikingly similar to those observed in human brains with Lewy pathology, neuronal degeneration, and motor defects, despite a lack of transgene expression in dopaminergic neurons of the substantia nigra pars compacta. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions in several muscles examined, suggesting that alpha-synuclein interfered with a universal mechanism of synapse maintenance. Thy1 transgene expression of wild-type human alpha-synuclein resulted in similar pathological changes, thus supporting a central role for mutant and wild-type alpha-synuclein in familial and idiotypic forms of diseases with neuronal alpha-synucleinopathy and Lewy pathology. These mouse models provide a means to address fundamental aspects of alpha-synucleinopathy and test therapeutic strategies.
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PMID:Neuropathology in mice expressing human alpha-synuclein. 1093 51

Dementia with Lewy bodies brains were immunohistochemically investigated using anti-synphilin-1 antibodies. The alpha-synuclein-positive brainstem type and well-defined cortical type Lewy bodies (LB) were positive for synphilin-1, while ill-defined LB and LB-related neurites were negative, suggesting that synphilin-1 does not directly associate with alpha-synuclein. Synphilin-1-positive LB were double-positive for phosphorylated neurofilament. In addition, tau-positive neurofibrillary tangles (NFT) were positive for synphilin-1, while neuropil threads were negative. Immunoelectron microscopically, synphilin-1 was located on filamentous components in cortical type LB and on paired helical filaments in NFT. It is likely that synphilin-1 accumulates in the cell body according to the axonal transport blockage, and associates with abnormal cytoskeltons during the formation of LB or NFT, suggesting that synphilin-1 is non-specifically implicated in the formation of different neuronal cytoskeletal inclusions.
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PMID:Immunohistochemical study of synphilin-1 in brains of patients with dementia with Lewy bodies - synphilin-1 is non-specifically implicated in the formation of different neuronal cytoskeletal inclusions. 1209 58

We provide an overview of synaptic pathology in dementia with Lewy bodies (DLB) and related neurodegenerative disorders that are characterised by intraneuronal accumulation of alpha-synuclein aggregates. The review addresses the clinico-neuropathological correlates of synaptic pathology in Lewy body disease, and concentrates on: altered alpha-synuclein metabolism, mechanisms leading to alpha-synuclein fibril formation (self-polymerisation, alpha-synuclein mutations and post-translational modifications) and how these influence the axonal transport and synaptic network in ageing and disease process. Understanding the mechanisms leading to intraneuronal alpha-synuclein accumulation are crucial for the development of novel therapies for treatment of Lewy body disease.
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PMID:Pathophysiology of synuclein aggregation in Lewy body disease. 1629 36


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