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)

Biological effects related to cell growth, as well as a role in the pathogenesis of Alzheimer disease, have been ascribed to the beta-amyloid precursor protein (beta-APP). Little is known, however, about the intracellular cascades that mediate these effects. We report that the secreted form of beta-APP potently stimulates mitogen-activated protein kinases (MAPKs). Brief exposure of PC-12 pheochromocytoma cells to beta-APP secreted by transfected Chinese hamster ovary cells stimulated the 43-kDa form of MAPK by > 10-fold. Induction of a dominant inhibitory form of ras in a PC12-derived cell line prevented the stimulation of MAPK by secreted beta-APP, demonstrating the dependence of the effect upon p21ras. Because the microtubule-associated protein tau is hyperphosphorylated in Alzheimer disease, we sought and found a 2-fold enhancement in tau phosphorylation associated with the beta-APP-induced MAPK stimulation. In the ras dominant inhibitory cell line, beta-APP failed to enhance phosphorylation of tau. The data presented here provide a link between secreted beta-APP and the phosphorylation state of tau.
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PMID:Secreted beta-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation. 804 53

The density of diffuse, primitive, classic and compact beta-amyloid (beta/A4) deposits was estimated in the hippocampus and adjacent gyri in human patients with Down's syndrome (DS) and sporadic Alzheimer's disease (AD). The objective of the study was to determine whether there were differences in beta/A4 deposition in DS and sporadic AD and whether these differences could be attributed to overexpression of the amyloid precursor gene (APP) in DS. Total beta/A4 deposit density was greater in DS than AD in all brain regions studied but the DS/AD density ratios varied between brain regions. In the majority of brain regions, the ratio of primitive to diffuse beta/A4 deposits was greater in DS but the ratio of classic to diffuse deposits was greater in AD. The data were consistent with the hypothesis that overexpression of the APP gene in DS may lead to increased beta/A4 deposition. However, local brain factors also appear to be important in beta/A4 deposition in DS. Overexpression of the APP gene may also be responsible for increased production of paired helical filaments (PHF) and result in enhanced formation of primitive beta/A4 deposits in DS. In addition, increased formation of classic deposits in AD suggests that factors necessary for the production of a compact amyloid core are enhanced in AD compared with DS.
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PMID:Differences in beta-amyloid (beta/A4) deposition in human patients with Down's syndrome and sporadic Alzheimer's disease. 804 69

A recent study has demonstrated an association of the apolipoprotein E allele epsilon 4 (APOE*4) to familial and sporadic late-onset Alzheimer's disease (AD). Also, in late-onset AD families linked to chromosome 19, the onset age decreased when the number of APOE*4 alleles increased. A similar effect of the APOE*4 genotype was observed in early-onset AD families linked to mutations in the APP gene located on chromosome 21. We assessed whether the APOE genotype had an influence on the age of onset of AD in chromosome 14 linked early-onset AD families. No significant effect of the APOE genotype on onset age could be detected.
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PMID:APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer's disease. 804 78

Overexpression of the beta-amyloid precursor protein gene (beta-APP) may contribute to the abnormal generation of beta-amyloid protein in Alzheimer's disease. We demonstrate using a human glial cell line (1321N1) that activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate (PMA) increases beta-APP mRNA levels, induces known components of the transcription factor activator protein-1 (AP-1), and increases protein-DNA binding activity to AP-1 sequences within the beta-APP promoter. A beta-APP promoter-luciferase reporter gene is transcriptionally activated by PMA, as well as by expression of constitutively activated PKC or by expression of c-Jun. Further characterization suggests that the distal but not the proximal AP-1 recognition site binds nuclear proteins regulated by PKC, and that the AP-1 binding activity is likely to be composed of Jun-Jun homodimers rather than Jun-Fos heterodimers. Additional studies demonstrate that a single copy of the distal AP-1 site fused to a heterologous promoter is sufficient to confer a response to PMA. Mutagenesis of this site in the beta-APP promoter renders it unresponsive to c-Jun and attenuates transcriptional activation by PMA. We suggest that cellular mediators that activate PKC, particularly those that induce significant increases in c-Jun, may up-regulate expression of the beta-APP gene and consequently affect production and processing of this protein.
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PMID:A direct role for protein kinase C and the transcription factor Jun/AP-1 in the regulation of the Alzheimer's beta-amyloid precursor protein gene. 806 12

The beta A4 peptide is the major constituent of the amyloid core of abundant senile plaques found in the cerebral cortex of patients with Alzheimer's disease. This amyloid peptide is synthesized as part of a large transmembrane amyloid protein precursor or APP. In addition to the highly expressed transmembrane APP isoforms, an mRNA encoding a secreted APP lacking the transmembrane domain has been identified. A cleavage of the transmembrane protein also yields an extracellular soluble APP fragment. The effect of phorbol esters on the release of the extracellular APP was studied in transfected Chinese hamster ovary cells which stably express either a transmembrane or a secreted APP isoform. The activation of protein kinase C by phorbol-12,13-dibutyrate increased the extracellular release of the transmembrane APP resulting from its proteolytic cleavage, while 4-beta-phorbol, which does not activate protein kinase C, did not significantly affect the recovery of the soluble APP. On the contrary, the recovery of APP secreted in the culture medium without proteolytic cleavage was not increased by protein kinase C-mediated phosphorylation.
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PMID:Activation of protein kinase C increases the extracellular release of the transmembrane amyloid protein precursor of Alzheimer's disease. 810 Apr 50

The beta-amyloid precursor protein (beta APP) is a widely expressed integral membrane protein that is proteolytically processed to yield several secreted derivatives, including soluble APP (APPs), the 4-kDa amyloid beta-peptide (A beta), and a related 3-kDa peptide (p3). To understand beta APP trafficking and processing, we analyzed the sorting of beta APP in Madin-Darby canine kidney (MDCK) cells, an epithelial cell known to possess physiologically distinct apical and basolateral plasma membranes. Processing of beta APP resulted in highly polarized secretion of APPs. More than 90% of APPs was detected in the basolateral compartment, and less than 10% was found in the apical compartment. This was associated with a preferential localization of beta APP on the basolateral cell surface. Activation of protein kinase C, which is known to enhance the secretion of APPs, did not change the polarity of APPs release but significantly increased the amount secreted. A beta and p3 peptides were also secreted predominantly basolaterally. In addition, MDCK cells secreted a truncated form of A beta beginning at Arg-5. These data show that the proteolytic processing products of beta APP undergo polarized secretion. Moreover, the results suggest that the amyloidogenic A beta peptide is generated following the polarized sorting of beta APP. The polarized basolateral secretion of A beta in these epithelial cells provides a potential mechanism for the accumulation of A beta in the abluminal basement membrane of brain microvessels during Alzheimer disease.
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PMID:Polarized secretion of beta-amyloid precursor protein and amyloid beta-peptide in MDCK cells. 810 45

Inherited Alzheimer's disease is a genetically heterogeneous disorder that involves gene defects on at least five chromosomal loci. Three of these loci have been found by genetic linkage studies to reside on chromosomes 21, 19, and 14. On chromosomes 21, the gene encoding the precursor protein of Alzheimer-associated amyloid (APP) has been shown to contain several mutations in exons 16 and 17 which account for roughly 2-3% of familial Alzheimer's disease (FAD). The other loci include what appears to be a susceptibility gene on chromosome 19 associated with late-onset (> 65 years) FAD, and a major early-onset FAD gene defect on the long arm of chromosome 14. In other early- and late-onset FAD kindreds, the gene defects involved do not appear to be linked to any of these three loci, indicating the existence of additional and as of yet unlocalized FAD genes. This review provides a historical perspective of the search for FAD gene defects and summarizes the progress made in world-wide attempts to isolate and characterize the genes responsible for this disorder.
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PMID:Genetic heterogeneity of gene defects responsible for familial Alzheimer disease. 812 74

beta-amyloid and ALZ-50 immunocytochemical reactivity were determined in the brains of rabbits fed either a control or 2% cholesterol diet. Control rabbits demonstrated no accumulation of intracellular immunolabeled beta-amyloid within 3 min after death. In animals fed the experimental diet for 4, 6, and 8 weeks (postmortem interval < 3 min), there was an increasingly mild-to-moderate-to-severe accumulation of intracellular immunolabeled beta-amyloid. Whether or not beta-amyloid is causally linked to processes leading to dementia, it is related in some way to the prime cause of human death; heart disease. Hypercholesterolemic rabbits may provide an animal model to study altered beta-APP metabolism leading to Alzheimer-like beta-amyloid accumulation xe03and extracellular deposition in brain.
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PMID:Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. 815 29

The 4-kDa beta-amyloid protein that forms fibrillar deposits in Alzheimer's diseased brains is derived from a large precursor, the beta-amyloid precursor protein (beta-APP). Recently, it has been reported that beta-amyloid is normally produced and secreted by cultured mammalian cells. In our studies involving recombinant expression of beta-APP, increased yields of beta-amyloid were associated with expression of aberrant beta-APP molecules. Deletion mutations within the beta-amyloid domain, incorrect beta-APP isoform expression in fibroblasts or neuronal cells, or excess amounts of beta-APP all led to increases in beta-amyloid production. Aberrant beta-APP appears to be diverted from the secretory pathway and then degraded to beta-amyloid.
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PMID:Increased amyloid production from aberrant beta-amyloid precursor proteins. 816 22

The main component of amyloid plaques in Alzheimer's disease (AD) is the beta-amyloid peptide (beta/A4), derived from beta-amyloid precursor proteins (beta-APPs). In order to identify proteases possibly involved in the cleavage at the N-terminal site of beta/A4 a chromogenic peptide corresponding to this region of beta-APP was used. Here the purification and characterization of a new human brain protease with the ability to cleave the beta-APP peptide as well as beta-APP in vitro are described. The enzyme has a molecular mass of 100 kDa and belongs likely to the class of metalloproteases. It should further be named "MP100". The enzyme has a very broad substrate specificity in vitro.
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PMID:Purification and characterization of a novel metalloprotease from human brain with the ability to cleave substrates derived from the N-terminus of beta-amyloid protein. 819 8


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