Binding of amyloid β precursor protein to coagulation factor XIa in vivo may favour haemorrhagic stroke

1998 ◽  
Vol 245 (2) ◽  
pp. 111-115 ◽  
Author(s):  
M. Bornebroek ◽  
Peter A. Kr. von dem Borne ◽  
Joost Haan ◽  
Joost C. M. Meijers ◽  
William E. Van Nostrand ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Coagulation Factor ◽  
Haemorrhagic Stroke ◽  
Precursor Protein ◽  
Factor Xia

Platelet coagulation factor XIa-inhibitor, a form of Alzheimer amyloid precursor protein

Science ◽  
1990 ◽  
Vol 248 (4959) ◽  
pp. 1126-1128 ◽  
Author(s):  
R. Smith ◽  
D. Higuchi ◽  
G. Broze
Keyword(s):  
Amyloid Precursor Protein ◽  
Coagulation Factor ◽  
Precursor Protein ◽  
Factor Xia

Thyroid Hormone Regulates Endogenous Amyloid-β Precursor Protein Gene Expression and Processing in Both In Vitro and In Vivo Models

Thyroid ◽  
2006 ◽  
Vol 16 (12) ◽  
pp. 1207-1213 ◽  
Author(s):  
Stephen A. O'Barr ◽  
Jin S. Oh ◽  
Chan Ma ◽  
Gregory A. Brent ◽  
James J. Schultz
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Protein Gene ◽  
Amyloid Β ◽  
Precursor Protein ◽  
In Vivo Models

scholarly journals Identification of an alpha-1 antitrypsin variant with enhanced specificity for factor XIa by phage display, bacterial expression, and combinatorial mutagenesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Varsha Bhakta ◽  
Mostafa Hamada ◽  
Amy Nouanesengsy ◽  
Jessica Lapierre ◽  
Darian L. Perruzza ◽  
...  
Keyword(s):  
Phage Display ◽  
Activated Protein C ◽  
Coagulation Factor ◽  
Bacterial Expression ◽  
Antithrombotic Agent ◽  
Expression Library ◽  
Factor Xia ◽  
Combinatorial Mutagenesis ◽  
Alpha 1 Antitrypsin

AbstractCoagulation Factor XIa (FXIa) is an emerging target for antithrombotic agent development. The M358R variant of the serpin alpha-1 antitrypsin (AAT) inhibits both FXIa and other proteases. Our aim was to enhance the specificity of AAT M358R for FXIa. We randomized two AAT M358R phage display libraries at reactive centre loop positions P13-P8 and P7-P3 and biopanned them with FXIa. A bacterial expression library randomized at P2′-P3′ was also probed. Resulting novel variants were expressed as recombinant proteins in E. coli and their kinetics of FXIa inhibition determined. The most potent FXIa-inhibitory motifs were: P13-P8, HASTGQ; P7-P3, CLEVE; and P2-P3′, PRSTE (respectively, novel residues bolded). Selectivity for FXIa over thrombin was increased up to 34-fold versus AAT M358R for these single motif variants. Combining CLEVE and PRSTE motifs in AAT-RC increased FXIa selectivity for thrombin, factors XIIa, Xa, activated protein C, and kallikrein by 279-, 143-, 63-, 58-, and 36-fold, respectively, versus AAT M358R. AAT-RC lengthened human plasma clotting times less than AAT M358R. AAT-RC rapidly and selectively inhibits FXIa and is worthy of testing in vivo. AAT specificity can be focused on one target protease by selection in phage and bacterial systems coupled with combinatorial mutagenesis.

The effect of corticosteroids on amyloid β precursor protein/amyloid precursor-like protein expression and processing in vivo

1999 ◽  
Vol 276 (1) ◽  
pp. 61-64 ◽  
Author(s):  
Grant Budas ◽  
Christine M Coughlan ◽  
Jonathan R Seckl ◽  
Kieran C Breen
Keyword(s):  
Protein Expression ◽  
Amyloid Β ◽  
Precursor Protein

Factor XIa Induced Activation of the Intrinsic Cascade In Vivo

1996 ◽  
Vol 75 (03) ◽  
pp. 445-449 ◽  
Author(s):  
Hugo ten Cate ◽  
Bart J Biemond ◽  
Marcel Levi ◽  
Walter A Wuillemin ◽  
Kenneth Bauer ◽  
...  
Keyword(s):  
Human Factor ◽  
Coagulation Factor ◽  
Thrombin Inhibitor ◽  
Bleeding Tendency ◽  
Loading Dose ◽  
Factor Xi ◽  
Factor Xia ◽  
Initial Activation ◽  
Baseline Values

SummaryCoagulation factor XI is a glycoprotein of the contact factor system. Its deficiency is associated with a highly variable bleeding tendency, thus a role in relation to hemostasis appears to exist. However, the importance of factor XI for stimulating intrinsic coagulation in vivo has not yet been determined. To study the procoagulant effects of human factor Xla in vivo, we infused the purified enzyme into normal chimpanzees (100 Μg) in the absence or presence of the thrombin inhibitor rec-hirudin (1.0 mg/kg loading dose plus 0.3 mg/kg body wt continuous infusion). Factor Xla elicited an immediate activation of factors IX, X, and prothrombin, as measured by their respective activation fragments. However, whereas the activation of factors IX and X was immediate and shortlasting, (peak increments of 6- and 1.4-fold of baseline at 5 minutes after injection), the conversion of prothrombin gradually increased, reaching a summit of 6-fold baseline values after 60 min, and remaining elevated during the course of the experiments. Thrombin-antithrombin complexes also remained elevated during the study period. In the presence of hirudin, the initial activation of factors IX, X, and prothrombin was unchanged, however the further increment in prothrombin fragment FI+2 was markedly inhibited. These results demonstrate that factor Xla is a potential agonist of the intrinsic cascade in vivo, which activity is enhanced in the presence of thrombin.

scholarly journals The cerebrospinal-fluid soluble form of Alzheimer's amyloid β is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex

1993 ◽  
Vol 293 (1) ◽  
pp. 27-30 ◽  
Author(s):  
J Ghiso ◽  
E Matsubara ◽  
A Koudinov ◽  
N H Choi-Miura ◽  
M Tomita ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Amyloid Fibrils ◽  
Membrane Attack Complex ◽  
Amyloid Β ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Neuritic Plaque ◽  
Soluble Form ◽  
Direct Binding

The amyloid fibrils deposited in Alzheimer's neuritic plaque cores and cerebral blood vessels are mainly composed of aggregated forms of a unique peptide, 39-42 amino acids long, named amyloid beta (A beta). A similar, although soluble, A beta (‘sA beta’) has been identified in cerebrospinal fluid, plasma and cell supernatants, indicating that it is normally produced by proteolytic processing of its precursor protein, amyloid precursor protein (APP). Using direct binding experiments we have isolated and characterized an 80 kDa circulating protein that specifically interacts with a synthetic peptide identical with A beta. The protein was unmistakably identified as SP-40,40 or ApoJ, a cytolytic inhibitor and lipid carrier, by means of amino acid sequence and immunoreactivity with specific antibodies. Immunoprecipitation with anti-SP-40,40 retrieved soluble A beta from cerebrospinal fluid, indicating that the interaction occurs in vivo.

scholarly journals Transgenic Expression of the Amyloid-β Precursor Protein-Intracellular Domain Does Not Induce Alzheimer's Disease–Like Traits In Vivo

PLoS ONE ◽  
2010 ◽  
Vol 5 (7) ◽  
pp. e11609 ◽  
Author(s):  
Luca Giliberto ◽  
Cristina d'Abramo ◽  
Christopher Michael Acker ◽  
Peter Davies ◽  
Luciano D'Adamio
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Intracellular Domain ◽  
Transgenic Expression

scholarly journals Antithrombotic Effects of Montelukast by Targeting Coagulation Factor XIa

2021 ◽  
Author(s):  
Dong Wang ◽  
Yang Zhou ◽  
Yingying Qi ◽  
Meiru Song ◽  
Huiqiao Yao ◽  
...  
Keyword(s):  
Oral Anticoagulants ◽  
Coagulation Factor ◽  
Healthy Individuals ◽  
Prevention Of Thrombosis ◽  
Factor Xia ◽  
Severe Hemorrhage ◽  
Antithrombotic Effects ◽  
Antiasthmatic Drug ◽  
Increase Blood Loss

Abstract Current oral anticoagulants prescribed for the prevention of thrombosis suffer from severe hemorrhagic problems. Coagulation factor XIa (FXIa) has been confirmed as a safer antithrombotic target as intervention with FXIa causes lower hemorrhagic risks. In this study, by a high-throughput virtual screening, we identified Montelukast (MK), an oral antiasthmatic drug, as a potent and specific FXIa inhibitor (IC50 = 0.17 µM). Compared with the two mostly prescribed anticoagulants (Warfarin and Apixaban), MK demonstrated comparable or even higher antithrombotic effects in three independent animal models. More importantly, in contrast to the severe hemorrhage caused by Warfarin or Apixaban, MK did not measurably increase blood loss in vivo. In addition, MK did not affect the hemostatic function in plasma from healthy individuals. In contrast, MK suppressed clot formation in clinical hypercoagulable plasma samples. This study provides a lead compound of anticoagulants targeting FXIa, and suggests the exploratory clinical researches on antithrombotic therapies using MK.

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