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)

The beta-amyloid precursor protein APP is generally accepted to be directly or indirectly involved in the neurodegenerative disorder Alzheimer's disease and has been extensively studied in a number of mammalian systems. Its normal function remains, however, still elusive. We have used the clawed toad, Xenopus laevis, to study the first non-mammalian APP protein. Screening of a Xenopus laevis intermediate pituitary cDNA library led to the identification of two structurally different APP gene transcripts presumably resulting from duplicated genes. Sequence comparison between the Xenopus and human APP proteins revealed at the amino acid sequence level an identity of 92%. Both Xenopus genes were found to be expressed in all tissues examined, but their expression levels differed among tissues. In addition, as in mammals, alternative splicing was observed and the alternatively spliced APP(695) mRNA variant was expressed predominantly in the brain and the oocyte, while the longer isoforms (APP(751-770)) were predominant in the other tissues examined. Of special interest is the finding that, like human but unlike mouse or rat beta-amyloid (Abeta), the Xenopus peptide contains all amino acid residues implicated in amyloidogenesis. We conclude that Xenopus APP mRNA is ubiquitously expressed and alternatively spliced, and that the highly conserved Xenopus APP protein contains an Abeta peptide with amyloidogenic potency.
Brain Res Mol Brain Res 2001 Dec 16
PMID:Expression of the gene encoding the beta-amyloid precursor protein APP in Xenopus laevis. 1174 58

The completion of the human genome sequence will greatly accelerate development of a new branch of bioscience and provide fundamental knowledge to biomedical research. We used the sequence information to measure replication timing of the entire lengths of human chromosomes 11q and 21q. Megabase-sized zones that replicate early or late in S phase (thus early/late transition) were defined at the sequence level. Early zones were more GC-rich and gene-rich than were late zones, and early/late transitions occurred primarily at positions identical to or near GC% transitions. We also found the single nucleotide polymorphism (SNP) frequency was high in the late-replicating and replication-transition regions. In the early/late transition regions, concentrated occurrence of cancer-related genes that include CCND1 encoding cyclin D1 (BCL1), FGF4 (KFGF), TIAM1 and FLI1, was observed. The transition regions contained other disease-related genes including APP associated with familial Alzheimer's disease (AD1), SOD1 associated with familial amyotrophic lateral sclerosis (ALS1) and PTS associated with phenylketonuria. These findings are discussed with respect to the prediction that increased DNA damage occurs in replication-transition regions. We propose that genome-wide assessment of replication timing serves as an efficient strategy for identifying disease-related genes.
Hum Mol Genet 2002 Jan 01
PMID:Chromosome-wide assessment of replication timing for human chromosomes 11q and 21q: disease-related genes in timing-switch regions. 1177 95

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. Recent estimates suggest that possibly over 70% of the genetic variance for the disease remains unaccounted for by apolipoprotein E (APOE) and the three known early-onset AD genes (APP, PSEN1, PSEN2). Specifically, one recent segregation analysis predicted the existence of up to four additional susceptibility genes having a similar or greater effect than APOE. However, most of the nearly three dozen putative AD loci proposed to date have only been inconsistently replicated in follow up analyses and more studies are necessary to distinguish false-positive findings from genuine signals. Novel AD genes will not only provide valuable clues for the development of novel therapeutic approaches, but will also allow the development of new genetic risk-profiling strategies that are an essential prerequisite for early prediction/prevention of this devastating disease. In this review, we will present a brief overview of analytic tools in complex disease genetics, as well as a summary of recent linkage and association findings indicating the existence of novel late-onset AD genes on chromosomes 12, 10, and 9.
J Mol Neurosci 2001 Oct
PMID:Dancing in the dark? The status of late-onset Alzheimer's disease genetics. 1181 86

Cell-culture studies have revealed some of the fundamental features of the interaction of amyloid Abeta with cells and the mechanism of amyloid accumulation and pathogenesis in vitro. A(beta)1-42, the longer isoform of amyloid that is preferentially concentrated in senile plaque (SP) amyloid deposits in Alzheimer's disease (AD), is resistant to degradation and accumulates as insoluble aggregates in late endosomes or lysosomes. Once these aggregates have nucleated inside the cell, they grow by the addition of aberrantly folded APP and amyloidgenic fragments of APP, that would otherwise be degraded, onto the amyloid lattice in a fashion analogous to prion replication. This accumulation of heterogeneous aggregated APP fragments and Abeta appears to mimic the pathophysiologyof dystrophic neurites, where the same spectrum of components has been identified by immunohistochemistry. In the brain, this residue appears to be released into the extracellular space, possibly by a partially apoptotic mechanism that is restricted to the distal compartments of the neuron. Ultimately, this insoluble residue may be further digested to the protease-resistant A(beta)n-42 core, perhaps by microglia, where it accumulates as senile plaques. Thus, the dystrophic neurites are likely to be the source of the immediate precursors of amyloid in the senile plaques. This is the opposite of the commonly held view that extracellular accumulation of amyloid induces dystrophic neurites. Many of the key pathological events of AD may also be directly related to the intracellular accumulation of this insoluble amyloid. The aggregated, intracellular amyloid induces the production of reactive oxygen species (ROS) and lipid peroxidation products and ultimately results in the leakage of the lysosomal membrane. The breakdown of the lysosomal membrane may be a key pathogenic event, leading to the release of heparan sulfate and lysosomal hydrolases into the cytosol. Together, these observations provide the novel view that amyloid deposits and some of the early events of amyloid pathogenesis initiate randomly within single cells in AD. This pathogenic mechanism can explain some of the more enigmatic features of Alzheimer's pathogenesis, like the focal nature of amyloid plaques, the relationship between amyloid, dystrophic neurites and neurofibrillary-tangle pathology, and the miscompartmentalization of extracellular and cytosolic components observed in AD brain.
J Mol Neurosci 2001 Oct
PMID:Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease. 1181 87

The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The mechanism underlying this increased risk is not completely clear, yet mounting evidence supports the idea that the ability of apoE to interact with the amyloid-beta (Abeta) peptide and influence its conformation and clearance plays a major role. Evidence to support this concept comes from in vitro and in vivo studies of apoE/Abeta interactions and the effects of these interactions on Abeta conformation and cellular clearance. Recent studies on the effect of murine and human apoE in APP transgenic mice provide direct evidence that apoE is critically involved in the in vivo converstion of Abeta into forms which contain high 5-sheet content and associated cellular toxicity (neuritic plaques and CAA). These studies also suggest a role for human apoE in Abeta clearance in vivo.
J Mol Neurosci 2001 Oct
PMID:Role of apoe/Abeta interactions in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy. 1181 88

Signaling via notch receptors and their ligands is an evolutionary ancient and highly conserved mechanism governing cell-fate decisions throughout the animal kingdom. Upon ligand binding, notch receptors are subject to a two-step proteolysis essential for signal transduction. First, the ectodomain is removed by an enzyme cleaving near the outer-membrane surface ("site2"). Consecutively, the notch intracellular domain is liberated by a second protease cutting within the transmembrane sequence ("site3"). The intracellular domain is then transferred to the nucleus to act as a transcriptional coactivator. The proteases involved in notch receptor activation are shared with other proteins undergoing regulated intramembrane proteolysis, with intriguing parallels to APP. Specifically, site3 cleavage of Notch, as well as gamma-secretase processing of APP depend both critically on presenilins 1 and 2. Moreover, ADAM 10 and ADAM 17, the proteases proposed to perform site2 cleavage, are also the most probable candidate alpha-secretases to cleave APP. While the biological significance of APP processing remains to be further elucidated, interference with notch signaling has been shown to have severe consequences both in small animal models as well as in humans. Thus, a growing number of long known genetic syndromes like Alagille syndrome or Fallot's tetralogy can be caused by mutations of genes relevant for the notch signaling pathway. Likewise, the anticipated interference of gamma-secretase inhibitors with site3 cleavage may turn out to be a major obstacle for this therapeutic approach to Alzheimer's disease.
J Mol Neurosci 2001 Oct
PMID:Implication of APP secretases in notch signaling. 1181 90

MDC9 (ADAM9/meltrin gamma) is a widely expressed and catalytically active metalloprotease-disintegrin protein that has been implicated in the ectodomain cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and as an alpha secretase for the amyloid precursor protein. In this study, we evaluated the expression of MDC9 during development and generated mice lacking MDC9 (mdc9(-/-) mice) to learn more about the function of this protein during development and in adults. During mouse development, MDC9 mRNA is ubiquitously expressed, with particularly high expression levels in the developing mesenchyme, heart and brain. Despite the ubiquitous expression of MDC9, mdc9(-/-) mice appear to develop normally, are viable and fertile, and do not have any major pathological phenotypes compared to wild-type mice. Constitutive and stimulated ectodomain shedding of HB-EGF is comparable in embryonic fibroblasts isolated from mdc9(-/-) and wild-type mice, arguing against an essential role of MDC9 in HB-EGF shedding in these cells. Furthermore, there were no differences in the production of the APP alpha and gamma secretase cleavage product (p3) and of beta- and gamma-secretase cleavage product (A beta) in cultured hippocampal neurons from mdc9(-/-) or wild-type mice, arguing against an essential major role of MDC9 as an alpha-secretase in mice. Further studies, including functional challenges and an evaluation of potential compensation by, or redundancy with, other members of the ADAM family or perhaps even with other molecules will be necessary to uncover physiologically relevant functions for MDC9 in mice.
Mol Cell Biol 2002 Mar
PMID:Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life. 1183 19

The amyloid precursor protein presents several cleavage sites leading to the release of its entire C-terminal domain into the cytoplasm. During apoptosis, this C-terminal domain can be cleaved at amino acid 664 by caspases 3, 6, and 8 and can thus generate two peptides N- and C-terminal to amino acid 664 (C31). Recently, it was shown that the C31 induces apoptosis after transfection into N2A and 293 T cell lines. We have analyzed here, by internalization into neurons, the physiological consequences of the entire C-terminal domain (APP-Cter) and of its membrane proximal sequence corresponding to the N-terminal peptide unmasked after caspase cleavage. We find that whereas micromolar concentrations of APP-Cter are harmless, the peptide extending from the membrane (amino acid 649) to the caspase cleavage site (amino acid 664) in the same range of concentrations induces DNA fragmentation, cleavage of actin at a caspase-sensitive site, and activates caspase 3. A mutated version of this sequence (tyrosine 653 replaced by an aspartate) abolishes the effect in vitro and in vivo. Taken together, this report suggests the existence of a new mechanism contributing to Alzheimer's Disease-associated cell death.
Mol Cell Neurosci 2001 Nov
PMID:A short cytoplasmic domain of the amyloid precursor protein induces apoptosis in vitro and in vivo. 1192 41

Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and anti-apoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [(N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S-enantiomer TV3279 [(N-Propargyl-(3S)Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The anti-apoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glyceraldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PKI 1195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by rasagiline and TV3326 is closely linked to the anti-apoptotic action of these drugs and their ability to process APP by activation of alpha-secretase.
Cell Mol Neurobiol 2001 Dec
PMID:Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. 1204 33

The nicotinic (nAChRs) and muscarinic (mAChRs) acetylcholine receptors and acetylcholinesterase (AChE) activity were studied in the brains of APP(SWE) transgenic mice (Tg+) and age-matched nontransgenic controls (Tg-) that were between 4 and 19 months of age. A significant increase in the binding of 125I-labeled alpha-bungarotoxin (alpha7 nAChRs) was observed in most brain regions analyzed in 4-month-old Tg+ mice, preceding learning and memory impairments and amyloid-beta (Abeta) pathology. The enhanced alpha7 receptor binding was still detectable at 17-19 months of age. Increase in [3H]cytisine binding (alpha4beta2 nAChRs) was measured at 17-19 months of age in Tg+ mice, at the same age when the animals showed heavy Abeta pathology. No significant changes in [3H]pirenzepine (M1 mAChRs) or [3H]AFDX 384 (M2 mAChRs) binding sites were found at any age studied. The upregulation of the nAChRs probably reflects compensatory mechanisms in response to Abeta burden in the brains of Tg+ mice.
Mol Cell Neurosci 2002 Jun
PMID:Selective nicotinic receptor consequences in APP(SWE) transgenic mice. 1209 66


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