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Biomedical subjects

E Koo

Publications and source records attributed to E Koo.

9 recordsLinked to original sources
PubMed2001

Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex.

Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, binds directly to epithelial cadherin (E-cadherin). This binding is mediated by the large cytoplasmic loop of PS1 and requires the membrane-proximal cytoplasmic sequence 604-615 of mature E-cadherin. This sequence is also required for E-cadherin binding of protein p120, a known regulator of cadherin-mediated cell adhesion. Using wild-type and PS1 knockout cells, we found that increasing PS1 levels suppresses p120/E-cadherin binding, and increasing p120 levels suppresses PS1/E-cadherin binding. Thus PS1 and p120 bind to and mutually compete for cellular E-cadherin. Furthermore, PS1 stimulates E-cadherin binding to beta- and gamma-catenin, promotes cytoskeletal association of the cadherin/catenin complexes, and increases Ca(2+)-dependent cell-cell aggregation. Remarkably, PS1 familial Alzheimer disease mutant DeltaE9 increased neither the levels of cadherin/catenin complexes nor cell aggregation, suggesting that this familial Alzheimer disease mutation interferes with cadherin-based cell-cell adhesion. These data identify PS1 as an E-cadherin-binding protein and a regulator of E-cadherin function in vivo.

Animals↗
PubMed2000

Amyloid-beta and treatment opportunities for Alzheimer's disease.

Proposed treatments of Alzheimer's disease (AD) are most likely to succeed if they are based on an understanding of the complex biology of AD and its effects on cognition. Treatments may target a single or multiple components of the complex pathology of AD with the hope that by affecting an individual component of AD pathology, the disease course can be affected. One such component is amyloid-beta (Abeta), a feature of the senile plaque. Abeta may be critical for inducing the pathology seen in AD. Accumulation of Abeta may result in a cascade of biochemical events leading to neuronal dysfunction, which may present opportunities for intervention at multiple different points to slow disease progression. Treatment may be directed towards decreasing Abeta production, increasing Abeta removal, and decreasing Abeta aggregation. Alternatively, treatment may be directed at more distal pathways by: modulating downstream events possibly due to Abeta such as free radical toxicity, decreasing inflammation, preventing cell membrane damage, restoring calcium homeostasis, preventing excitotoxicity, and blocking the cellular response to injury by inhibiting neuronal apoptosis. This review underscores the complex biology of Abeta specifically looking at the potential targets of therapeutics based on emerging knowledge of this biology.

Journal Article↗
PubMed1999

The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons.

The normal functional neurobiology of the Alzheimer's disease (AD) related gene presenilin 1 (PS1) is unknown. One clue comes from a genetic screen of Caenorhabditis elegans, which reveals that the presenilin homologue sel-12 facilitates lin-12 function [D. Levitan, I. Greenwald, Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene, Nature 377 (1995) 351-355]. The mammalian homologue of lin-12, Notch1, is a transmembrane receptor that plays an important role in cell fate decisions during development, including neurogenesis, but does not have a known function in fully differentiated cells. To better understand the potential role of Notch1 in mammalian postmitotic neurons and to test the hypothesis that Notch and PS 1 interact, we studied the effect of Notch1 transfection on neurite outgrowth in primary cultures of hippocampal/cortical neurons. We demonstrate that Notch1 inhibits neurite extension, and thus has a function in postmitotic mature neurons in the mammalian CNS. Furthermore, we present evidence demonstrating that there is a functional interaction between PS1 and Notch1 in mammalian neurons, analogous to the sel-12/lin-12 interaction in vulval development in C. elegans [D. Levitan, T. Doyle, D. Brousseau, M. Lee, G. Thinakaran, H. Slunt, S. Sisodia, I. Greenwald, Assessment of normal and mutant human presenilin function in Caenorhabditis elegans, Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 14940-14944; D. Levitan, I. Greenwald, Effect of Sel-12 presenilin on Lin-12 localization and function in Caenorhabditis elegans, Development, 125 (1998) 3599-3606]. The inhibitory effect of Notch1 on neurite outgrowth is markedly attenuated in neurons from PS1 knockout mice, and enhanced in neurons from transgenic mice overexpressing wild type PS1, but not mutant PS1. These data suggest that PS1 facilitates Notch1 function in mammalian neurons, and support the hypothesis that a functional interaction exists between PS1 and Notch1 in postmitotic mammalian neurons.

Alzheimer Disease↗
PubMed1996

Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues.

Mutations in genes encoding related proteins, termed presenilin 1 (PS1) and presenilin 2 (PS2), are linked to the majority of cases with early-onset familial Alzheimer's disease (FAD). To clarify potential function(s) of presenilins and relationships of presenilin expression to pathogenesis of AD, we examined the expression of PS1 and PS2 mRNA and PS1 protein in human and mouse. Semi-quantitative PCR of reverse-transcribed RNA (RT-PCR) analysis revealed that PS1 and PS2 mRNA are expressed ubiquitously and at comparable levels in most human and mouse tissues, including adult brain. However, PS1 mRNA is expressed at significantly higher levels in developing brain. In situ hybridization studies of mouse embryos revealed widespread expression of PS1 mRNA with a neural expression pattern that, in part, overlaps that reported for mRNA encoding specific Notch homologs. In situ hybridization analysis in adult mouse brain revealed that PS1 and PS2 mRNAs are enriched in neurons of the hippocampal formation and entorhinal cortex. Although PS1 and PS2 mRNA are expressed most prominently in neurons, lower but significant levels of PS1 and PS2 transcripts are also detected in white matter glial cells. Moreover, cultured neurons and astrocytes express PS1 and PS2 mRNAs. Using PS1-specific antibodies in immunoblot analysis, we demonstrate that PS1 accumulates as approximately 28 kDa N-terminal and approximately 18 kDa C-terminal fragments in brain. Immunocytochemical studies of mouse brain reveal that PS1 protein accumulates in a variety of neuronal populations with enrichment in somatodendritic and neuropil compartments.

Adult↗
PubMed1994

High free and latent collagenase activity in psoriatic arthritis synovial fluids.

Collagenase activity has been studied intensively in SF from OA and RA patients. Less is known about collagenolytic activity in PsA SF. Therefore we examined collagenolytic activity in crude and trypsin treated SF as well as the alpha 1-antitrypsin and alpha 2-macroglobulin concentrations in 50 patients suffering from OA (n = 13), RA (n = 17), and PsA (n = 20). Free collagenolytic activity was low in the crude OA SF (1.80 +/- 1.35 micrograms released collagen/min/ml SF) and almost equally low in RA SF (2.35 +/- 1.80 micrograms released collagen/min/ml SF; P > 0.3). The PsA SF, however, exhibited a significantly higher free collagenolytic activity (5.63 +/- 5.69 micrograms released collagen/min/ml SF; P < 0.05 in comparison to OA and RA SF). The treatment of the SF with trypsin further activated collagenolytic activity in each group (OA 2.17 +/- 1.35 micrograms released collagen/min/ml SF; RA 6.48 +/- 6.73 micrograms released collagen/min/ml SF; PsA 11.24 +/- 5.02 micrograms released collagen/min/ml SF) and yielded significant differences between OA and RA, OA and PsA, and RA and PsA SF (P < 0.05). Concomitantly with the collagenolytic activity, the alpha 1-antitrypsin and alpha 2-macroglobulin concentrations of the SF were measured. In SF from patients with PsA (172.9 +/- 69.4 mg/100 ml) and RA (190.6 +/- 64.7 mg/100 ml) the alpha 1-antitrypsin was significantly higher than in those from OA SF (106.1 +/- 39.2 mg/100 ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

A pharmacokinetic approach to the study of cell membrane lithium transport in vivo.

Although many previous investigations have focused on in vitro studies of lithium transport by erythrocytes (RBCs) of psychiatric patients, the extent to which such studies actually reflect the transport of this drug by other types of cells in vivo is unknown. To study lithium transport in vivo, pharmacokinetic analysis of plasma lithium concentration data was performed in four subjects who were given single oral doses of lithium carbonate (600 mg). The data were analyzed according to a two-compartment model, consisting of a central compartment (extracellular, including plasma) and a peripheral (intracellular) compartment. Rate constants for the transfer of lithium into (ki) and out of (ko) the intracellular compartment were calculated. In RBCs from the same subjects, lithium transport in vitro was also directly measured. Rate constants were determined for phloretin-sensitive transport (ks), which corresponds to Na+-Li+ countertransport activity, and residual passive "leak" diffusion (kr). In RBCs, these two pathways account for major components of lithium efflux and influx, respectively. To compare the in vivo and in vitro rate constant data, the ratios ko/ki and ks/kr were also calculated. There was a significant correlation between these two rate-constant ratios (r = 0.96, p less than 0.05), although the values observed in vitro were higher than those found in vivo. Because the in vivo rate constants reflect lithium transport by many types of cells in the peripheral compartment, this finding supports the idea that the RBC may provide a useful model for studying lithium transport processes that are also operative in other types of cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Membrane Permeability↗