Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We determined the concentration of the messenger RNA species which encode four (m1-m4) of the five cloned muscarinic receptors in brains of Alzheimer's disease patients as compared to age-matched controls. Assays were performed using the quantitative method of DNA-excess solution hybridization in the cerebral cortex (frontal, temporal and occipital), hippocampus, nucleus basalis of Meynert and brainstem. The results suggest a statistically significant decrease in the m1 muscarinic receptor message in the temporal and occipital cortex, with no change in other regions. There was no change in the level of mRNA encoding the m2, m3 or m4 receptors in any of the brain regions studied.
Brain Res Mol Brain Res 1992 Nov
PMID:Comparison of the concentration of messenger RNA encoding four muscarinic receptor subtypes in control and Alzheimer brains. 133 1

In this immunohistopathological study alpha 1-antichymotrypsin, which is barely demonstrable in the normal brain, was found in amyloid fibrils, endothelial cells and the cytoplasm of astroglial cells in brains from patients with Alzheimer's disease. Amyloid precursors stained with methenamine silver were arrayed mainly along the membranes, and amyloid fibrils, which stained densely with anti-alpha 1-antichymotrypsin, were in direct contact with the fibrous structures connecting with the membranes of vascular feet or astrocytic processes. From the above findings, alpha 1-antichymotrypsin seems to play a role in the production of amyloid fibrils in Alzheimer's disease.
Virchows Arch B Cell Pathol Incl Mol Pathol 1992
PMID:The distribution of alpha 1-antichymotrypsin and amyloid production in the brain in Alzheimer's disease. 134 95

A cDNA clone that was isolated from a human substantia innominata cDNA library is described. By Northern hybridization analysis, a 15.5 kilobase (kb) transcript was identified by this clone in RNA samples from several brain regions, but not in RNA samples from white matter, liver or placenta. Hybridization to human genomic DNA revealed a pattern indicative of a single copy gene. DNA sequence analysis showed 3.0 kb of 3' untranslated region with no significant open reading frame. An additional cDNA clone, representing a section of an alternate form of this transcript, was isolated that contained an additional 1.5 kb at the 3' end. Using a nuclease protection assay, the expression of this gene was found to be increased by 30% in Alzheimer disease temporal cortex RNA samples compared to temporal cortex RNA samples from normal controls, but to be at equivalent levels in Alzheimer disease, as compared to normal control, substantia innominata RNA samples. This assay also showed that this gene was expressed at 3.5-fold higher levels in normal substantia innominata than in normal cerebellum. In situ hybridization analysis showed that the transcript could be detected in cerebellar neurons.
Brain Res Mol Brain Res 1992 Jan
PMID:Identification and characterization of a large human brain gene whose expression is increased in Alzheimer disease. 137 73

Cerebrospinal Fluid (CSF) levels of the main metabolites of monoamines (MHPG, 5-HIAA, and HVA) were measured in patients with early onset (AD) and late-onset (SDAT) Alzheimer's disease, vascular dementia (VD), and elderly controls. Psychobehavioral assessment was carried out by means of MMSE and GBS. Mean MHPG levels did not differ from controls; 5-HIAA was lower in VD when compared to both controls and SDAT. HVA was decreased in AD, SDAT, and VD with respect to controls. Significant correlations between HVA and psycho-behavioral parameters were observed in SDAT and VD groups, whereas no relationship was documented in AD. The SDAT group was divided in SDAT-A (age at onset: greater than 65 less than or equal to 80 yr) and SDAT-B (age at onset: greater than 80 yr). SDAT-A had significantly lower CSF HVA values than SDAT-B (165 +/- 64 vs 235.7 +/- 85). SDAT-B HVA levels were similar to those observed in controls. Correlation analysis between HVA and neuropsychological variables was significant in SDAT-A, but not in SDAT-B. These results might support the evidence of SDAT heterogeneity.
Mol Chem Neuropathol
PMID:CSF monoamine metabolites in old age dementias. 138 90

An immunohistochemical analysis utilizing antibodies to glial fibrillary acid protein (GFAP), microglia, beta-amyloid, amyloid P-component, neurofibrillary tangles (NFT), and microtubule associated protein-tau (MAP-tau) was performed on the cholinergic basal forebrain in Alzheimer's disease (AD). This severely compromised system, which includes the nucleus basalis of Meynert, is largely responsible for the massive loss of cortical and subcortical cholinergic innervation in the diseased state. Our study juxtaposes the basal forebrain immunohistopathology to the hippocampus, amygdala, and entorhinal cortex in AD. Key findings include a progressive degeneration of these cholinergic neurons characterized by the formation of immunoreactively atypical NFT, the loss of intraneuronal lipofuscin, a lack of senile plaque and beta-amyloid deposition within the basal forebrain, and end-stage gliosis without residual extracellular NFT. These structural and compositional differences suggest a unique pathogenesis of the basal forebrain separate from other cortical regions in AD.
Mol Chem Neuropathol 1992 Aug
PMID:Immunohistochemical analysis of the basal forebrain in Alzheimer's disease. 138 47

We determined the oxidative phenotype and metabolic ratio of debrisoquine in 96 Chinese patients with Alzheimer's disease (n = 12), Parkinson's disease (n = 55), and using patients with stroke and cervical spondylosis as controls (n = 29). We did not find any difference in debrisoquine metabolic phenotype among Parkinson's disease, Alzheimer's disease, and control patients as judged by chi-square analysis. In addition, the metabolic ratio of all our patients was less than 12.6. The result suggested that Chinese patients with Parkinson's disease and Alzheimer's disease metabolize debrisoquine at a velocity not different from that of their Western counterparts even though the frequency distribution of debrisoquine metabolism phenotyping in these two populations is quite different.
Mol Chem Neuropathol 1992 Aug
PMID:Debrisoquine metabolism in Chinese patients with Alzheimer's and Parkinson's diseases. 138 49

Reduction of the cerebral metabolic rate of glucose is one of the most predominant abnormalities generally found in the Alzheimer brain, whereas the cerebral metabolic rate of oxygen is only slightly diminished or not at all the beginning of this dementive disorder. This metabolic abnormality may induce severe functional disturbances, obviously preceding morphobiological changes. From the cerebral metabolic rates of oxidized glucose and oxygen, the cerebral ATP formation rate was calculated in incipient early-onset, incipient late-onset and stable advanced dementia of Alzheimer type. A reduction of ATP formation was found from at least 7% in incipient early-onset, to around 20% in incipient late-onset DAT, and from 35% to more than 50% in stable advanced dementia. This approximation was adjusted to findings demonstrating diminished activities of enzymes active in glucose metabolism and formation of oxidation equivalents for ATP production from substrates other than glucose. A reduction for energy formation to the same range was found, as was also recently reported, in vivo in Alzheimer patients. From this rather theoretical point of view, a permanent loss of energy by at least 7-20% in incipient and progressively advancing dementia of the Alzheimer type may be assumed, with an increasing tendency in stable advanced dementia to around 50% energy loss. This energy deficit may have drastic impacts on brain function.
Mol Chem Neuropathol 1992 Jun
PMID:Oxidative energy metabolism in Alzheimer brain. Studies in early-onset and late-onset cases. 141 18

Protease nexin-II (PN-II) is a potent chymotrypsin inhibitor that forms SDS-stable inhibitory complexes with epidermal growth factor binding protein, the gamma-subunit of nerve growth factor, and trypsin, and represents the secreted form of the amyloid beta-protein precursor (APP) that contains the Kunitz-type protease inhibitor domain. To determine the expression of PN-II within the peripheral nervous system, human dorsal root ganglia were processed for immunocytochemistry using well-characterized monoclonal antibodies against PN-II and for in situ hybridization studies using 35S-RNA PN-II probes for both APP751 and APP770. Highly specific immunoperoxidase staining of PN-II was demonstrated within the cytoplasm of dorsal root ganglia neurons and their processes in cryostat (fresh frozen) and vibratome (paraformaldehyde-fixed) sections. In situ hybridization using an anti-sense 35S-RNA PN-II probe demonstrated the presence of intense neuronal labeling. Labeling was not observed when the corresponding sense 35S-RNA PN-II probe was used. Although the precise functional role of PN-II/APP is not clear, the accumulation of amyloid beta-protein within the neuropil appears to be one of the earliest events in the pathogenesis of Alzheimer's disease (AD). Thus knowledge of the cell populations expressing the PN-II/APP gene would certainly be helpful for studies of the molecular mechanisms leading to the morphological and functional changes of AD. The results of this study clearly establish the expression of PN-II and its mRNA within the dorsal root ganglia neurons and their processes, and provide another point of departure for studies of the molecular mechanisms underlying the deposition of amyloid beta-protein and its relationships to the formation of neuritic plaques and neurofibrillary tangles.
Mol Chem Neuropathol 1992 Jun
PMID:Expression of protease nexin-II in human dorsal root ganglia. A correlative immunocytochemical and in situ hybridization study. 141 19

The deposition of amyloid protein aggregates in brain is the main pathological feature of Alzheimer's disease. Their principal constituent is a peptide termed beta A4, which comprises up to 43 amino acid residues. It is highly insoluble under physiological conditions and aggregates into filaments that form very dense clusters in vivo and in vitro. Based on a beta A4 prototype sequence spanning residues 10 to 42 or 43, we have designed analogues in which hydrophobic amino acid residues in position 17 to 20 were substituted by more hydrophilic residues. Depending on the kind of newly introduced amino acids and their position within the sequence, the substitution of only two residues led to variants exhibiting a broad spectrum of different properties. Common to them was a reduced beta-sheet content after solubilization in water and in the solid state. Some of the variants showed significantly reduced amyloidogenicity: although still forming filaments, they did not aggregate into the highly condensed depositions that are typical for amyloid. In addition, they could be solubilized in 200 mM-NaCl and KCl. When mixed with beta A4 peptides bearing the natural sequence, two of the analogues could inhibit the formation of filaments in vitro. These results demonstrate that a well-preserved hydrophobic core around residues 17 to 20 of beta A4 is crucial for the formation of beta-sheet structure and the amyloid properties of beta A4. The introduction of structural alterations within this region may guide the development of reagents for the therapy of Alzheimer's disease.
J Mol Biol 1992 Nov 20
PMID:Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer's disease beta A4 peptides. 145 57

Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) (or familial cerebral amyloid angiopathy) and familial Alzheimer's disease (FAD) share several properties. Both are autosomal dominant forms of cerebral amyloidosis characterized by beta-amyloid (A beta) deposition. In HCHWA-D the A beta is predominantly found in blood vessels and in early parenchymal plaques, whereas in AD parenchymal A beta deposits in the form of senile plaques and neurofibrillary tangles are a more prominent finding. Point mutations in the amyloid precursor protein (APP) have recently been described, in both conditions. A G to C transversion at codon 618 (extracellular portion of APP695), producing a single amino acid substitution of glutamine instead of glutamine acid, occurs in HCHWA-D; whereas mutations at codon 642 in the intramembrane region of APP695 (phenylalanine, isoleucine, or glycine instead of valine) are associated with early onset FAD. This suggests that the site of particular mutations in the APP gene and the type of amino acid substitution in the APP holoprotein are more important in determining clinicopathological phenotype and age at which A beta is deposited. Thus FAD and HCHWA-D can be regarded as two sides of the same coin.
Mol Neurobiol 1992
PMID:Molecular biology of Alzheimer's amyloid--Dutch variant. 146 89


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