A-Beta Metabolism and Alzheimer's Disease - T. Saido (Landes, 2003) WW

180 Pages·2003·4.72 MB·English

Aβ Metabolism
and Alzheimer's Disease

Takaomi Comings Saido

LANDES BIOSCIENCE
EUREKAH.COM

Takaomi Comings Saido
Laboratory for Proteolytic Neuroscience
RIKEN Brain Science Institute
Wako-shi, Saitama, Japan

Aβ Metabolism
and Alzheimer’s Disease

NEUROSCIENCE
INTELLIGENCE
UNIT 7

EUREKAH.COM
AUSTIN, TEXAS
U.S.A.

LANDES BIOSCIENCE
GEORGETOWN, TEXAS
U.S.A.

Neuroscience Intelligence Unit 7

Eurekah.com
Landes Bioscience

Copyright ©2003 Eurekah.com
All rights reserved.
No part of this book may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopy, recording, or any information storage and retrieval system,
without permission in writing from the publisher.
Printed in the U.S.A.

Please address all inquiries to the Publishers:
Eurekah.com / Landes Bioscience, 810 South Church Street
Georgetown, Texas, U.S.A. 78626
Phone: [phone]; FAX: [phone]
www.Eurekah.com
www.landesbioscience.com

While the authors, editors and publisher believe that drug selection and dosage and the specifications
and usage of equipment and devices, as set forth in this book, are in accord with current recommend-
ations and practice at the time of publication, they make no warranty, expressed or implied, with
respect to material described in this book. In view of the ongoing research, equipment development,
changes in governmental regulations and the rapid accumulation of information relating to the biomedical
sciences, the reader is urged to carefully review and evaluate the information provided herein.

Library of Congress Cataloging-in-Publication Data

CIP applied for but not received at time of publication.

ISBN: 1-58706-230-5

Aβ METABOLISM AND ALZHEIMER’S DISEASE

Designed by Celeste Carlton

Dedication

To the late George F. Comings (1931-2002)*
Rotarian
and
My American Father,
Husband of Dorothy J. Comings
and
Father of Stephen & Benjamin Comings

* The Comings family gave me an international outlook on life when I lived with them as a high
school exchange student in Corinth, New York, U.S.A., in 1976-1977.

This Page Intentionally Left Blank

CONTENTS

1. Overview—Aβ Metabolism: From Alzheimer Research
to Brain Aging Control ..........................................................................1
Takaomi C. Saido
Introduction .......................................................................................... 1
Etiology of AD ...................................................................................... 3
Aβ versus Tau ....................................................................................... 7
Aβ Metabolism: Three Major Targets ................................................... 7
Questions Regarding the Mechanisms of the Cascade
of Aβ-Initiated Pathology ................................................................ 10
Animal Models of AD: The Issues to be Further Addressed ................. 10
Towards the Scientific Control of Brain Aging .................................... 12
Final Comments.................................................................................. 14

2. β-Secretase: Progress and Open Questions ...........................................17
Martin Citron
Abstract ............................................................................................... 17
Identification of β-Secretase ................................................................ 17
Characterization of β-Secretase ............................................................ 19
BACE2, the Closest Relative ............................................................... 20
BACE1 Transgenics and Knockouts .................................................... 21
β-Secretase Drug Development Is Under Way .................................... 22
Controversies and Open Questions ..................................................... 22

3. APP α-Secretase, a Novel Target for Alzheimer Drug Therapy ............ 27
Shoichi Ishiura, Masashi Asai, Chinatsu Hattori, Nika Hotoda,
Beata Szabo, Noboru Sasagawa and Sei-ichi Tanuma
Abstract ............................................................................................... 27
Introduction ........................................................................................ 27
ADAMs and α-Secretase ..................................................................... 28
Relations between α- and Other Secretases.......................................... 30
Future Perspectives .............................................................................. 31

4. γ-Secretase and Presenilin.....................................................................33
Michael S. Wolfe
Abstract ............................................................................................... 33
Introduction ........................................................................................ 33
Substrate Specificity and Intramembrane Proteolysis ........................... 34
Inhibitor Studies Suggest an Aspartyl Protease Mechanism.................. 35
The Presenilin/γ-Secretase Connection: AD-Causing Mutations
and Knockout Mice......................................................................... 36
Presenilin Topology and Maturation ................................................... 37
Presenilins: Intramembrane-Cleaving Aspartyl Proteases ..................... 38
Biological Roles of γ-Secretases ............................................................ 39
Objections to the Presenilin as Protease Hypothesis ............................ 41
Nicastrin and Other Putative Members of the γ-Secretase Complex .... 41
An Emerging Family of Polytopic Membrane Proteases ...................... 42
Future Directions ................................................................................ 43

5. Functional Roles of APP Secretases ...................................................... 49
Dieter Hartmann
Abstract ............................................................................................... 49
Introduction: Cleavage of APP is a Special Case of Regulated
Intramembrane Proteolysis .............................................................. 49
α-Secretase .......................................................................................... 51
β-Secretase .......................................................................................... 54
γ-Secretase ........................................................................................... 54
Summary............................................................................................. 55

6. Proteolytic Degradation of Aβ by Neprilysin
and Other Peptidases ...........................................................................61
Takaomi C. Saido and Hiroyuki Nakahara
Abstract ............................................................................................... 61
Introduction: Why Aβ Degradation? ................................................... 61
Two Major Categories of Aβ-Degrading Mechanisms ......................... 62
Identification of Neprilysin as a Major in vivo Aβ-Degrading
Enzyme in Brain.............................................................................. 63
Region-Specific Decline of Neprilysin Expression and Activity
in Brain Upon Aging ....................................................................... 68
Utilization of Neprilysin Activity for Prevention and Therapy
of AD .............................................................................................. 70
Other Aβ-Degrading Enzyme Candidates ........................................... 73
Human Genetics of Risk and Anti-Risk Factors for AD:
A Proposal for Multi-Component Analysis ...................................... 74

7. Aβ Degradation by Endothelin-Converting Enzymes ...........................81
Elizabeth A. Eckman and Christopher B. Eckman
Abstract ............................................................................................... 81
Introduction: The Endothelin-Converting Enzymes ........................... 81
Both ECE-1 and ECE-2 Are Expressed in Brain.................................. 82
A Potential Role for Endothelin-Converting Enzymes
in Aβ Catabolism ............................................................................ 82
The Serendipitous Discovery of Metalloproteases as Important
Modulators of Aβ Concentration in vivo ......................................... 83
Phosphoramidon Increases Aβ Concentration in CNS-Derived
Cell Lines Through the Inhibition of Intracellular Degradation ...... 84
Endothelin-Converting Enzymes: Potential Targets
for the Phosphoramidon-Mediated Increase
in Aβ Concentration ....................................................................... 85
Overexpression of Endothelin-Converting Enzyme-1 Results
in a Significant Decrease in Extracellular Aβ Concentration that
Is Completely Reversed by Treatment with Phosphoramidon ......... 86

Increased Removal of Exogenous Aβ Is Apparent Only
in ECE-1a Transfected Cells ........................................................... 87
Recombinant ECE-1 Degrades Aβ in vitro.......................................... 88
Kinetic Analysis of Aβ40 Cleavage by solECE-1.................................. 88
Current Studies in Animal Models ...................................................... 88
Summary: ECE Activity May Be One of Many Regulators
of Aβ Accumulation in the Brain..................................................... 89
The Regulation of Endogenous ECE Activity Is Complex,
and Alterations May Influence Susceptibility
to Alzheimer’s Disease ..................................................................... 89
Increased ECE Activity May Be Therapeutic
for Alzheimer’s Disease .................................................................... 90
The Clinical Use of ECE Inhibitors Must Be
Considered Carefully ....................................................................... 90

8. Aβ Metabolism in Cholesterol Enriched
Membrane Microdomains ....................................................................95
Todd E. Golde and M. Paul Murphy
Abstract ............................................................................................... 95
Introduction ........................................................................................ 95
CEMs as a Generic Term for Cholesterol Enriched
Membrane Microdomains ............................................................... 96
Aβ Production in CEMs ..................................................................... 96
Aβ Deposition, Aggregation and CEMs .............................................. 99
ApoE, Cholesterol and CEMs ............................................................. 99
Aβ Degrading Enzymes in CEMs ...................................................... 100
Summary........................................................................................... 100

9. Amyloid β-Protein in Low-Density Membrane Domains...................105
Maho Morishima-Kawashima and Yasuo lhara
Abstract ............................................................................................. 105
Introduction ...................................................................................... 105
Age-Dependent Aβ Accumulation and Deposition
in the Human Brain ...................................................................... 106
Insoluble Aβ Is Located in LDM Domains........................................ 106
Aβ Accumulation in LDM Domains Accurately Reflects
the Extent of Aβ Deposition in the Brain ...................................... 108
Effects of Mutant Presenilin on the Aβ in LDM Domains ................ 110
Aβ Production by LDM Domains..................................................... 110
Possible Involvement of LDM-Aβ in Aβ Accumulation
in the Brain ................................................................................... 113

10. Transport-Clearance Hypothesis for Alzheimer’s Disease
and Potential Therapeutic Implications ............................................. 117
Berislav V. Zlokovic and Blas Frangione
Abstract ............................................................................................. 117
Introduction ...................................................................................... 117
Genetic Risk Factors for AD.............................................................. 117
Amyloid β Peptide ............................................................................ 118
A Clearance Mechanism .................................................................... 118
Aβ Transport out of the CNS ........................................................... 119
Plasma Aβ Transport......................................................................... 121
Immunization Strategies and Transport............................................. 122
Nonspecific Transport ....................................................................... 122
Transport-Based Strategies ................................................................ 122

11. Potential Role of Endogenous and Exogenous Aβ Binding
Molecules in Aβ Clearance and Metabolism.......................................127
Ronald B. DeMattos, Kelly R. Bales, Steven M. Paul
and David M. Holtzman
Abstract ............................................................................................. 127
Introduction ...................................................................................... 127
Animal Models of AD ....................................................................... 128
Aβ Peptide Metabolism in Human.................................................... 130
Aβ Metabolism in Wild Type and Transgenic Mouse Models
of Alzheimer’s Disease ................................................................... 131
Apolipoprotein E and Clusterin: In vivo Aβ Chaperone Proteins ...... 133
Exogenous Aβ Binding Proteins ........................................................ 137
Summary........................................................................................... 138

12. Modulating Amyloid-β Levels by Immunotherapy:
A Potential Therapeutic Strategy for the Prevention
and Treatment of Alzheimer’s Disease ...............................................145
Cynthia A. Lemere, Timothy J. Seabrook, Melitza Iglesias,
Chica Mori, Jodi F. Leverone and Edward T. Spooner
Abstract ............................................................................................. 145
Aβ Immunotherapy Prevents or Reduces AD Pathology
and Improves Behavioral Deficits in Transgenic
Mouse Models of AD .................................................................... 145
Characterization of the Mouse Immune Response
to Aβ Vaccination ......................................................................... 147
Immunization Strategies in Mice ....................................................... 151
Proposed Mechanisms for the Beneficial Effects
of Aβ Vaccination in Mice ............................................................ 153
Aβ Vaccination in Human Clinical Trials ......................................... 155
Future Strategies in AD Vaccine Development .................................. 156

Index ..................................................................................................163

Takaomi Comings Saido
Laboratory for Proteolytic Neuroscience
RIKEN Brain Science Institute
Wako-shi, Saitama, Japan
email: