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N G Irving

Publications and source records attributed to N G Irving.

17 recordsLinked to original sources
PubMed2000

Fe65 and X11beta co-localize with and compete for binding to the amyloid precursor protein.

The Fe65s and X11s are two families of adaptor proteins that bind to the Alzheimer's disease amyloid precursor protein (APP). Although both the X11s and Fe65s bind to similar regions of APP, they have opposing effects on Abeta production and hence may represent novel therapeutic targets. However, there is no evidence that the Fe65s and X11s are present within the same cell type or cell compartment and are thus capable of competing for binding to APP. Here we show that in neurones and transfected cells, APP, Fe65 and X11beta show overlapping subcellular distributions. Furthermore, we demonstrate that Fe65 and X11beta compete for binding to APP.

Amyloid beta-Protein Precursor↗
PubMed1999

Mint2/X11-like colocalizes with the Alzheimer's disease amyloid precursor protein and is associated with neuritic plaques in Alzheimer's disease.

Aberrant metabolism of the amyloid precursor protein (APP) is believed to be at least part of the pathogenic process in Alzheimer's disease. The carboxy-terminus of APP has been shown to interact with the Mint/X11 family of phosphotyrosine binding (PTB) domain-bearing proteins. It is via their PTB domains that the Mints/X11s bind to APP. Here we report the cloning of full-length mouse Mint2 and demonstrate that in primary cortical neurons, Mint2 and APP share highly similar distributions. Mint2 also colocalizes with APP in transfected CHO cells. In Mint2/APP-cotransfected cells, Mint2 reorganizes the subcellular distribution of APP and also increases the steady-state levels of APP. Finally, we demonstrate that Mint2 is associated with the neuritic plaques found in Alzheimer's disease but not with neurofibrillary tangles. These results are consistent with a role for Mint2 in APP metabolism and trafficking, and suggest a possible role for the Mints/X11s in the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed1997

Tau phosphorylation in transgenic mice expressing glycogen synthase kinase-3beta transgenes.

In order to investigate the effect on tau of manipulating glycogen synthase kinase (GSK)-3beta activity in the brain, we created transgenic mice harbouring wild-type GSK-3beta genes or a mutant GSK-3beta that is predicted to be more active. Transgene-derived mRNAs were detected in the brains of a number of the transgenic mouse lines and several of these transgenic lines displayed transgenic GSK-3beta activity. Western blot analyses of the two lines with the highest levels of transgenic GSK-3beta activity revealed that the phosphorylation status of tau was elevated at the AT8 epitope. These observations strongly suggest that GSK-3beta is an in vivo tau kinase in the brain. Only low levels of expression of GSK-3beta were obtained and it is possible that high levels of GSK-3beta activity are lethal.

Animals↗
PubMed1997

Overexpression of the mouse dishevelled-1 protein inhibits GSK-3beta-mediated phosphorylation of tau in transfected mammalian cells.

Tau is a neuronal microtubule-associated protein whose function is modulated by phosphorylation. GSK-3beta is a tau kinase. GSK-3beta is part of the wingless signalling pathway and stimulation by wingless is predicted to down-regulate GSK-3beta activity. In Drosophila imaginal disc cells, overexpression of dishevelled, a component of the wingless pathway, mimics the wingless signal. We have therefore studied the effect that overexpression of the murine dishevelled-1 protein has on GSK-3beta-mediated phosphorylation of tau in transfected CHO cells. We find that co-transfection with dishevelled-1 is inhibitory to GSK-3beta-mediated tau phosphorylation. Tau is hyperphosphorylated in Alzheimer's disease and the possible relevance of these findings to Alzheimer's disease pathogenesis are discussed.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Tau phosphorylation in cells transfected with wild-type or an Alzheimer's disease mutant Presenilin 1.

We have studied the effect of overexpressing either wild-type or an Alzheimer's disease mutant Presenilin 1 (PS1) on tau phosphorylation in transfected Chinese hamster ovary (CHO) and COS cells. Tau transfected into these cells is predominantly non-phosphorylated at many PHF-tau sites but co-transfection with the tau kinase glycogen synthase kinase-3 beta (GSK-3 beta) induces phosphorylation that generates epitopes for several phosphorylation-dependent antibodies. Co-transfection of tau with either wild-type or mutant PS1 did not alter tau phosphorylation as detected by five different antibodies. Likewise, co-transfection of the PS1s did not influence GSK-3 beta-mediated tau phosphorylation. The implications of these results for the pathogenesis of Alzheimer's disease are discussed.

Alzheimer Disease↗
PubMed1995

A mouse model for Down syndrome exhibits learning and behaviour deficits.

Trisomy 21 or Down syndrome (DS) is the most frequent genetic cause of mental retardation, affecting one in 800 live born human beings. Mice with segmental trisomy 16 (Ts65Dn mice) are at dosage imbalance for genes corresponding to those on human chromosome 21q21-22.3--which includes the so-called DS 'critical region'. They do not show early-onset of Alzheimer disease pathology; however, Ts65Dn mice do demonstrate impaired performance in a complex learning task requiring the integration of visual and spatial information. The reproducibility of this phenotype among Ts65Dn mice indicates that dosage imbalance for a gene or genes in this region contributes to this impairment. The corresponding dosage imbalance for the human homologues of these genes may contribute to cognitive deficits in DS.

Alzheimer Disease↗
PubMed1994

Gene order is conserved within the human chromosome 21 linkage group on mouse chromosome 10.

One hundred progeny from each of two intersubspecific mouse backcrosses were used to construct a comparative genetic map of a region of mouse chromosome 10 (MMU10) that is homologous to the distal tip of the long arm of human chromosome 21 (HSA21). The analysis included five genes and three simple sequence repeat markers, two of which flanked the HSA21-homologous cluster on either side. Analysis of 200 backcross progeny detected at least one crossover between each pair of adjacent genes and demonstrated that the proximal to distal orientation of the cluster was reversed between human and mouse. The order was determined to be Fyn-1-D10Mit20-S100b-Col6a1-Itgb2-Pfkl+ ++/D10Mit7-D10Mit11. Comparative mapping supports the order of corresponding markers on HSA21 determined using pulsed-field gel electrophoresis and radiation hybrid line data. However, sequence tagged site content mapping of human yeast artificial chromosomes (YACs) yielded conflicting data on the relative positions of human COL6A1 and S100B on HSA21. This discrepancy was resolved here by demonstrating that several key YACs used in the human contig analysis were mistyped for S100B. The murine map reported here provides a scaffold for construction of physical maps and yeast artificial chromosome contigs that will be useful in the development of mouse models for the study of Down syndrome.

Animals↗
PubMed1993

The positions of 12 simple sequence repeat markers relative to reference loci on mouse chromosome 16.

The genetic map positions of 12 simple sequence repeat (SSR) markers spanning mouse Chromosome (Chr) 16 were determined relative to reference markers on that chromosome. Interval mapping data were obtained with a panel of DNAs from two intersubspecific backcrosses. All but one of the markers were typed by us of nonradioactive polymerase chain reaction (PCR) products analyzed on agarose gels. The marker order was determined to be Prm-1, D16Mit9, Igl-1, D16Mit29, D16Mit1/D16Mit2, Smst, D16Mit4, D16Mit11, Gap43, D16Mit14, D16Mit30, D16Mit5, Pit-1, D16Mit27, D16H21S16 (formerly D21S16h), D16Mit19, App, D16Mit7, Sod-1. Two of these markers mapped to the known human Chr 21 (HSA21)/Chr 16 conserved linkage group. Nine additional SSR markers could not be typed because they were not polymorphic (four markers), did not amplify MOLD/Rk DNA (three markers), or failed to give PCR products under a range of conditions (two markers). A subset of the most robust SSRs provide a useful marker set for the analysis of previously unmapped crosses.

Animals↗
PubMed1993

Segmental trisomy as a mouse model for Down syndrome.

Mice trisomic for Chromosome (Chr) 16 have been used extensively as an animal model for human Down Syndrome (Trisomy 21). This system has drawbacks, however: trisomy for all of Chr 16 is incompatible with postnatal survival and produces trisomy for many more genes than those conserved in human Chr 21. We report here the development and preliminary characterization of mice that are trisomic for only the segment of mouse Chr 16 that is conserved in human Chr 21. While these segmentally trisomic mice, Ts(17(16)) 65Dn, do not appear to have all the features characteristic of Down Syndrome, they represent a mouse model that survives to adulthood and may be useful to study features of Down Syndrome that develop later in life, such as susceptibility to infection, increased incidence of leukemia, and Alzheimer-like neuropathology.

Animals↗
PubMed1991

Mouse chromosome-specific markers generated by PCR and their mapping through interspecific backcrosses.

We have utilized an oligonucleotide primer from the 3' end of the mouse L1 repeat element for amplification of mouse-specific inter-repeat PCR products from Chinese hamster/mouse somatic cell hybrids. PCR of a Chinese hamster/mouse somatic cell hybrid (96AZ2), containing only mouse chromosome 16, produced a range of mouse-specific bands. Two of the mouse-specific PCR products, of 250 and 580 bp, have been confirmed as originating from mouse chromosome 16 by somatic cell hybrid analysis. Both the 250- and 580-bp PCR products have been sequenced and demonstrate the expected sequence organization. Furthermore, both the 250- and 580-bp markers have been genetically mapped in detail to mouse chromosome 16 by direct hybridization to inter-repeat PCR products of progeny DNAs from Mus domesticus/Mus spretus interspecific backcrosses.

Animals↗
PubMed1991

The multipoint genetic mapping of mouse chromosome 16.

Utilizing a Mus spretus/Mus domesticus (C57BL/10) interspecific backcross, we have constructed a multipoint genetic map of mouse chromosome 16 that extends 43.2 cM from the proximal Prm-1 locus to the distal Ets-2 locus. The genetic map incorporates three new markers: D16Smh6, a random genomic clone; Pgk-1ps1, a phosphoglycerate kinase pseudogene; and the growth-associated protein Gap43. The map position of Gap43 indicates the presence, on mouse chromosome 16, of a significant-size conserved linkage group with human chromosome 3.

Animals↗
PubMed1989

The alpha 2 chain of type 1 collagen does not map to mouse chromosome 16 but maps close to the Met proto-oncogene on mouse chromosome 6.

The gene locus for the alpha 2 chain of type 1 collagen (Cola-2) was previously assigned to chromosome 16. Here we demonstrate, utilising both somatic cell hybrid analysis and genetic linkage analysis, in an interspecific Mus domesticus x Mus spretus cross that Cola-2 fails to cosegregate with mouse chromosome 16, but is linked to the Met proto-oncogene on chromosome 6.

Animals↗