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Vol. 1, No. 4-5, 2004
Issue release date: November 2004
Neurodegenerative Dis 2004;1:168–174
(DOI:10.1159/000080982)

BACE1 and Presenilin: Two Unusual Aspartyl Proteases Involved in Alzheimer’s Disease

Dominguez D.-I. · Hartmann D. · De Strooper B.
Neuronal Cell Biology and Gene Transfer Laboratory, Department of Human Genetics, KU Leuven and VIB4, Leuven, Belgium
email Corresponding Author

Abstract

Two enzymatic activities are required to generate the pathogenic β-amyloid (Aβ) peptide that accumulates in the brain of Alzheimer’s disease patients. Both activities are carried out by two unusual aspartyl proteases known as β- and γ-secretase. Their therapeutic inhibition appears, therefore, a promising strategy to treat the disease. Transgenic mouse models in which the genes encoding the secretases have been ablated offer an invaluable tool, on the one hand, to gain more insights into the biological function of these proteases and, on the other hand, to predict the consequences that might be associated with enzyme inhibition in vivo.


 goto top of outline Key Words

  • Alzheimer’s disease
  • Knockout mice
  • β-Secretase
  • =γ-Secretase

 goto top of outline Abstract

Two enzymatic activities are required to generate the pathogenic β-amyloid (Aβ) peptide that accumulates in the brain of Alzheimer’s disease patients. Both activities are carried out by two unusual aspartyl proteases known as β- and =γ-secretase. Their therapeutic inhibition appears, therefore, a promising strategy to treat the disease. Transgenic mouse models in which the genes encoding the secretases have been ablated offer an invaluable tool, on the one hand, to gain more insights into the biological function of these proteases and, on the other hand, to predict the consequences that might be associated with enzyme inhibition in vivo.

Copyright © 2004 S. Karger AG, Basel


 goto top of outline References
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 goto top of outline Author Contacts

Diana-Ines Dominguez
Molecular Genetics Section, VIB4, Departement Menselijke Erfelijkheid, O. & N.
Herestraat 49, bus 602, BE–3000 Leuven (Belgium)
Tel. +32 16 345878, Fax +32 16 347181
E-Mail Diana-Ines.Dominguez@med.kuleuven.ac.be


 goto top of outline Article Information

Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 0, Number of References : 81


 goto top of outline Publication Details

Neurodegenerative Diseases

Vol. 1, No. 4-5, Year 2004 (Cover Date: Released November 2004)

Journal Editor: R.M. Nitsch, Zürich; C. Hock, Zürich
ISSN: 1660–2854 (print), 1660–2862 (Online)

For additional information: http://www.karger.com/ndd


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Two enzymatic activities are required to generate the pathogenic β-amyloid (Aβ) peptide that accumulates in the brain of Alzheimer’s disease patients. Both activities are carried out by two unusual aspartyl proteases known as β- and γ-secretase. Their therapeutic inhibition appears, therefore, a promising strategy to treat the disease. Transgenic mouse models in which the genes encoding the secretases have been ablated offer an invaluable tool, on the one hand, to gain more insights into the biological function of these proteases and, on the other hand, to predict the consequences that might be associated with enzyme inhibition in vivo.



 goto top of outline Author Contacts

Diana-Ines Dominguez
Molecular Genetics Section, VIB4, Departement Menselijke Erfelijkheid, O. & N.
Herestraat 49, bus 602, BE–3000 Leuven (Belgium)
Tel. +32 16 345878, Fax +32 16 347181
E-Mail Diana-Ines.Dominguez@med.kuleuven.ac.be


 goto top of outline Article Information

Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 0, Number of References : 81


 goto top of outline Publication Details

Neurodegenerative Diseases

Vol. 1, No. 4-5, Year 2004 (Cover Date: Released November 2004)

Journal Editor: R.M. Nitsch, Zürich; C. Hock, Zürich
ISSN: 1660–2854 (print), 1660–2862 (Online)

For additional information: http://www.karger.com/ndd


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Vassar R: Beta-secretase (BACE) as a drug target for Alzheimer’s disease. Adv Drug Deliv Rev 2002;54:1589–1602.
  2. Annaert W, Cupers P, Saftig P, De Strooper B: Presenilin function in APP processing. Ann NY Acad Sci 2000;920:158–164.
  3. Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G: Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 1999;14:419–427.
  4. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, John V: Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999;402:537–540.
  5. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M: Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999;286:735–741.
  6. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME: Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 1999;402:533–537.
  7. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F: Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998;391:387–390.
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