Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002395 (Alzheimer's disease)
 110,584 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and neuropathological findings of a 63-year-old male and a 25-year-old female with Down's syndrome are presented. Neuropathological examination of the older patient revealed intense features of Alzheimer's disease or senile dementia, including congophilic angiopathy and extensive mineral deposits in the globus pallidus and in the white matter of the cerebellum. In the hippocampus of the younger patient, plaque-like bodies and a few neurofibrillary tangles were found. From a survey of the cases hitherto reported in the literature it appears that among patients over 50 years of age it is common to encounter pathological features typical of Alzheimer's disease or senile dementia, that plaque-like bodies may occur in the second decade, neurofibrillary tangles in the third decade and a congophilic angiopathy in the fourth decade. The congophilic angiopathy is a frequent finding. Due to their high frequency, calcium or calciumlike deposits are regarded as important histopathological substrates of Down's syndrome. The clinical symptomatology of the long-surviving patients with Down's syndrome is that of a non-characteristic brain aging process and differs from that of the typical Alzheimer's disease. Organic dementia is not regularly found. Altogether, the anatomical findings in adult patients with Down's syndrome indicate a premature aging of the brain, which becomes more significant and widespread with increasing age.
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PMID:[Cerebral degeneration in Down's syndrome]. 15 70

A 68-year-old man, after having been diagnosed as having hepatic disease at about the age of 41 years, had been hospitalized frequently until his death. Blood sugar, iron, and copper had not increased during his illness. Although the diagnosis of liver cirrhosis had been made and he had been receiving therapy, various neurologic symptoms without disturbances of consciousness appeared six months before his death. Autopsy revealed hemochromatosis, liver cirrhosis, and pancreatic fibrosis. A large amount of iron had accumulated in the liver, the pancreas, and the thyroid gland, while considerable numbers of ceroid and lipofuscin pigment granules had accumulated diffusely in the brain. Abnormal astrocytes of the Alzheimer II type were diffusely distributed in the brain and contained no intranuclear glycogen which stained positive with the carmine stain. No spongy changes were seen in the deeper layers of the cerebral cortex. Chemical analyses for trace metals in the brain, liver, and kidneys revealed a large amount of iron and increased copper in the liver, and considerable quantities of copper, manganese, calcium, and mercury in the brain. Because of changes in the erythrocyte sedimentation rate and marked thymol turbidity seen before and after the occurrence of the neurologic symptoms, this man was suspected of having disorders of the trace-metal binding proteins and/or of their polymers.
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PMID:Hemochromatosis associated with brain lesions--a disorder of trace-metal binding proteins and/or polymers? 92 21

Catecholamine axons have been visualized in human cerebral cortex obtained during routine neurosurgical operations. The fluorescence histochemical method of Lindvall et al. was used, slightly modified (calcium-deprived buffer, glyoxylic acid fixation followed by formaldehyde vapours exposition). The frontal cortex was more richely provided with catecholamine terminals than the parietal cortex. Two general types of axon morphology are evident. The most frequent is thin and sinous, sometimes forming clews, or loose basket-like arrangement around presumed nerve cells. The other one is moniliform and demonstrates spherical evenly-spaced varicosities. They look like, respectively, the well characterized dopaminergic and noradrenergic axons of the rat cerebral cortex. In two cases of Alzheimer's disease, noradrenergic-like fibers were missing and voluminous green-fluorescent varicosities, sometimes in obvious connection with typical axons, were observed in the proximity of senile plaques.
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PMID:[Catecholaminergic axons in the human cerebral cortex. Observation by histofluorescence of cerebral biopsies in 2 cases of Alzheimer's disease]. 96 15

Abnormal phosphorylation of the microtubule associated protein tau component of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) may result from alterations in protein kinase expression. Calcium/calmodulin dependent protein kinase II (CaM kinase II) has been shown to phosphorylate tau in vitro in such a way to decrease its electrophoretic mobility. A68, apparently a modified form of tau in AD brain, also shows abnormal phosphorylation and slower mobility than tau. To further examine the role of CaM kinase II in AD, in situ hybridization studies were performed on tissues from rat, monkey and human to examine and compare the patterns of CaM kinase II mRNA expression in different brain regions. The most notable differences among the three species were observed in dendrites in layer I of isocortex, in the molecular layer of the dentate gyrus and stratum radiatum and stratum lacunosum-moleculare in hippocampus, where hybridization was detected in rat, but not in monkey or human brain. In addition, comparisons between tau and CaM kinase II mRNA expression were made in tissue from normal aged adults and AD patients, especially in areas prone to NFT formation. CaM kinase II and tau mRNAs were co-expressed in many neuronal populations, both those which are prone to NFT formation as well as those which are rarely affected by AD changes. No major differences in the relative abundance of either CaM kinase II or tau mRNA within particular neuronal populations was noted between normal aged and AD brain. Diminished hybridization was associated with serve neuronal pathology and cell loss.
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PMID:In situ hybridization of calcium/calmodulin dependent protein kinase II and tau mRNAs; species differences and relative preservation in Alzheimer's disease. 131 9

Cells from the olfactory epithelium of adult human cadavers have been propagated in primary culture and subsequently cloned. These cells exhibit neuronal properties including: neuron-specific enolase, olfactory marker protein, neurofilaments, and growth-associated protein 43. Simultaneously, the cells exhibit nonneuronal properties such as glial fibrillary acidic protein and keratin, the latter suggesting properties of neuroblasts or stem cells. These clonal cultures contain 5-10% of cells sufficiently differentiated to show odorant-dependent cyclic adenosine 3',5'-monophosphate (cAMP) or calcium-release responses when challenged with submicromolar concentrations of odorants. The potential of culturing neuronal cells from patients with neuropsychiatric disorders, such as Alzheimer's disease or schizophrenia, could enable the study of the pathophysiology of these neurons in the culture dish and allow new approaches to the study of mental illness.
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PMID:Continuous culture of neuronal cells from adult human olfactory epithelium. 132 Sep 21

A decrement in glucose utilization in brain was previously demonstrated in Alzheimer's disease (AD) and this abnormality has been proposed to play a role in the process of neuronal degeneration. We now report that glucose deprivation in cultured hippocampal neurons can result in antigenic alterations similar to those seen in AD neurofibrillary tangles (NFT) and, ultimately, cell death. Hypoglycemia caused an increase in neuronal immunoreactivity toward tau and ubiquitin antibodies. The antigenic alterations resulted from hypoglycemia-induced elevations in intracellular calcium levels as measured using the calcium indicator dye fura-2. The increased intraneuronal calcium levels, increased tau and ubiquitin immunoreactivities, and neuronal damage resulted from influx through the plasma membrane since they were not observed when cells were incubated in calcium-deficient medium. Neuronal damage and NFT-like antigenic changes were completely prevented by nerve growth factor (NGF) and basic fibroblast growth factor (bFGF), but not by epidermal growth factor (EGF). NGF and bFGF, but not EGF, prevented the aberrant rise in intracellular calcium levels that normally resulted from glucose deprivation. These data are consistent with the possibility that reduced glucose availability to neurons may contribute to the neuronal degeneration that occurs in AD. They also suggest that growth factors may normally protect neurons against hypoglycemic damage.
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PMID:Glucose deprivation elicits neurofibrillary tangle-like antigenic changes in hippocampal neurons: prevention by NGF and bFGF. 132 83

We reviewed computerized tomograms (CT) for basal ganglia and dentate nucleus calcifications in 79 patients with Parkinson's disease (PD), 54 patients with Alzheimer's disease (AD) and 109 controls aged 50 or more. When it was determined, no patient had disturbances in calcium metabolism. We found: (1) 30 subjects out of 242 (12.3%) with calcification located within the lenticular nucleus in 28. (2) Calcifications were unilateral in 11 and asymmetric in 11. (3) The prevalence of calcifications was 21.5% in PD, 9.2% in AD and 7.3% in controls and were significantly more severe in PD than in C and AD (P less than 0.02). (4) PD patients with calcifications were clinically indistinguishable from those without calcification. (5) Calcifications within the basal ganglia were not associated with a levodopa-resistance. We suggest the basal ganglia calcifications are more frequent in PD, but we cannot explain why, since post-synaptic lesions have never been showed in PD.
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PMID:Parkinson's disease and basal ganglia calcifications: prevalence and clinico-radiological correlations. 132 10

Quantitative receptor autoradiography was used to examine the density and distribution of [3H]kainic acid and [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) binding sites in the hippocampal formation and parahippocampal gyrus obtained at autopsy from 10 Alzheimer's disease and eight normal control individuals. In control and Alzheimer's disease individuals, [3H]kainic acid saturation binding analysis in the outer molecular layer of the dentate gyrus fitted a single-site model. Added calcium ions did not alter the density of [3H]kainic acid binding in the human tissues. These results suggest that calcium-sensitive high-affinity kainic acid binding sites are not present in the human brain in contrast to kainic acid receptors in the rat brain. [3H]AMPA binding was also slightly different in the human brain as compared to the rat, being greatest in the inner third as compared to the outer two-thirds of the dentate gyrus molecular layer. In both control and Alzheimer's disease individuals, [3H]kainic acid and [3H]AMPA binding densities were similar at anterior and posterior levels of the hippocampal formation. In Alzheimer's disease patients, there was a significant increase in [3H]AMPA binding in the infragranular layer. In some, but not all Alzheimer's disease patients, there was an increase in [3H]kainic acid binding densities in the outer half of the dentate gyrus molecular layer. The same individuals which exhibited an increase in [3H]kainic acid binding in the outer molecular layer also displayed increased [3H]AMPA binding in the hilar region. Similar alterations in [3H]kainic acid binding have been observed in rats which had received fimbria-fornix lesions, a model of chronic epilepsy and in individuals with temporal lobe epilepsy. Advanced Alzheimer's disease patients are at risk of developing seizures. The results suggest that several factors including cortical and subcortical pathology and seizure activity may contribute to the alterations in [3H]kainic acid and [3H]AMPA binding observed in the hippocampal formation in Alzheimer's disease.
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PMID:Hippocampal excitatory amino acid receptors in elderly, normal individuals and those with Alzheimer's disease: non-N-methyl-D-aspartate receptors. 132 33

Ca2+/calmodulin-dependent protein kinase II (CaMKII) exhibits a broad substrate specificity and regulates diverse responses to physiological changes of intracellular Ca2+ concentrations. Five isozymic subunits of the highly abundant brain kinase are encoded by four distinct genes. Expression of each gene is tightly regulated in a cell-specific and developmental manner. CaMKII immunoreactivity is broadly distributed within neurons but is discretely associated with a number of subcellular structures. The unique regulatory properties of CaMKII have attracted a lot of attention. Ca2+/calmodulin-dependent autophosphorylation of a specific threonine residue (alpha-Thr286) within the autoinhibitory domain generates partially Ca(2+)-independent CaMKII activity. Phosphorylation of this threonine in CaMKII is modulated by changes in intracellular Ca2+ concentrations in a variety of cells, and may prolong physiological responses to transient increases in Ca2+. Additional residues within the calmodulin-binding domain are autophosphorylated in the presence of Ca2+ chelators and block activation by Ca2+/calmodulin. This Ca(2+)-independent autophosphorylation is very rapid following prior Ca2+/calmodulin-dependent autophosphorylation at alpha-Thr286 and generates constitutively active, Ca2+/calmodulin-insensitive CaMKII activity. Ca(2+)-independent autophosphorylation of CaMKII also occurs at a slower rate when alpha-Thr286 is not autophosphorylated and results in inactivation of CaMKII. Thus, Ca(2+)-independent autophosphorylation of CaMKII generates a form of the kinase that is refractory to activation by Ca2+/calmodulin. CaMKII phosphorylates a wide range of neuronal proteins in vitro, presumably reflecting its involvement in the regulation of diverse functions such as postsynaptic responses (e.g. long-term potentiation), neurotransmitter synthesis and exocytosis, cytoskeletal interactions and gene transcription. Recent evidence indicates that the levels of CaMKII are altered in pathological states such as Alzheimer's disease and also following ischemia.
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PMID:Regulation and role of brain calcium/calmodulin-dependent protein kinase II. 133 43

In Alzheimer's disease (AD), abnormal accumulations of beta-amyloid are present in the brain and degenerating neurons exhibit cytoskeletal aberrations (neurofibrillary tangles). Roles for beta-amyloid in the neuronal degeneration of AD have been suggested based on recent data obtained in rodent studies demonstrating neurotoxic actions of beta-amyloid. However, the cellular mechanism of action of beta-amyloid is unknown, and there is no direct information concerning the biological activity of beta-amyloid in human neurons. We now report on experiments in human cerebral cortical cell cultures that tested the hypothesis that beta-amyloid can destabilize neuronal calcium regulation and render neurons more vulnerable to environmental stimuli that elevate intracellular calcium levels. Synthetic beta-amyloid peptides (beta APs) corresponding to amino acids 1-38 or 25-35 of the beta-amyloid protein enhanced glutamate neurotoxicity in cortical cultures, while a peptide with a scrambled sequence was without effect. beta APs alone had no effect on neuronal survival during a 4 d exposure period. beta APs enhanced both kainate and NMDA neurotoxicity, indicating that the effect was not specific for a particular subtype of glutamate receptor. The effects of beta APs on excitatory amino acid (EAA)-induced neuronal degeneration were concentration dependent and required prolonged (days) exposures. The beta APs also rendered neurons more vulnerable to calcium ionophore neurotoxicity, indicating that beta APs compromised the ability of the neurons to reduce intracellular calcium levels to normal limits. Direct measurements of intracellular calcium levels demonstrated that beta APs elevated rest levels of calcium and enhanced calcium responses to EAAs and calcium ionophore. The neurotoxicity caused by EAAs and potentiated by beta APs was dependent upon calcium influx since it did not occur in calcium-deficient culture medium. Finally, the beta APs made neurons more vulnerable to neurofibrillary tangle-like antigenic changes induced by EAAs or calcium ionophore (i.e., increased staining with tau and ubiquitin antibodies). Taken together, these data suggest that beta-amyloid destabilizes neuronal calcium homeostasis and thereby renders neurons more vulnerable to environmental insults.
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PMID:beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. 134 2


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