Pharmacological Mechanisms in Alzheimer's Therapeutics

337 Pages·2007·3.05 MB·English

by  A. Claudio Cuello

Pharmacological Mechanisms
in Alzheimer’s Therapeutics
A. Claudio Cuello
Pharmacological
Mechanisms in
Alzheimer’s Therapeutics
A.Claudio Cuello
Department of Pharmacology and Therapeutics
McGill University
Montreal,Quebec
Canada
ISBN-13:978-0-387-71521-6 e-ISBN-13:978-0-387-71522-3
Library ofCongress Control Number:2007926249
© 2007 Springer Science +Business Media,LLC
All rights reserved.This work may not be translated or copied in whole or in part without the
written permission ofthe publisher (Springer Science +Business Media,LLC,233 Spring Street,
New York,NY 10013,USA),except for brief excerpts in connection with reviews or scholarly
analysis. Use in connection with any form of information storage and retrieval, electronic
adaptation,computer software,or by similar or dissimilar methodology now known or hereafter
developed is forbidden.
The use in this publication oftrade names,trademarks,service marks,and similar terms,even if
they are not identified as such,is not to be taken as an expression of opinion as to whether or
not they are subject to proprietary rights.
9 8 7 6 5 4 3 2 1
Printed on acid-free paper.
springer.com
Forewords
Alzheimer’s disease is poised to create a global public health crisis. A 2005
Lancet report estimated that 24.3 million people worldwide currently have
dementia,and somewhere in the world,someone develops dementia every 7s.
The Lancet study projected that the global total will nearly double every 20
years,to 42.3 million in 2020 and 81.1 million in 2040.In the USA alone,an
estimated 5.1 million Americans have Alzheimer’s today,including 200,000–
500,000 individuals younger than 65 years with some form of early-onset
dementia.That number represents a 10% increase over the previous 2002 esti-
mate. Currently, one in eight Americans aged 65 or older has Alzheimer’s,
and nearly half of Americans aged 85 or older have the disease.
A major factor in this skyrocketing prevalence is the unprecedented gray-
ing of the global population. In 2006,78.2 million American baby boomers
(those born between 1946 and 1964) began turning 60 at the rate of 330 per
hour.World Population Ageing,a 2002 United Nations report,found that
● Population aging is a pervasive,irreversible,worldwide phenomenon.
● By 2050,the number of persons aged 60 and older will exceed the number
of persons under the age of 15,for the first time in human history.
● In the more-developed countries, one-fifth of the population was aged
over 60 in 2000;by 2050,one-third will be 60 or older in these regions.In
the less-developed world,8% of residents are currently aged over 60,and
that proportion will reach 20% by 2050.
● The world’s fastest-growing age group is “oldest old”individuals aged 80
and older.
These historic demographic shifts not only bring unprecedented numbers of
people into the age groups at greatest risk for Alzheimer’s but also strain the
ability of families and social systems to provide the care,support,and health
services they need.
Developing disease-modifying treatments for Alzheimer’s will be a critical
part of an effective global response to this impending crisis.We are extremely
fortunate that a committed international research community is gaining
insight into the fundamental neurobiology of the brain and pathological
v
vi Forewords
processes are implicated in Alzheimer’s at an unprecedented rate. I applaud
the authors and editor of Pharmacological Mechanisms in Alzheimer’s
Therapeuticsfor this very thorough and informative overview of some of the
most promising current pathways to intervention.
The array of therapeutic approaches discussed here represents the kind of
potentially broad pharmacological armamentarium we will need to address a
complex, multifactorial condition such as Alzheimer’s. A truly successful
treatment protocol will likely include a mix of agents aimed at several patho-
logical mechanisms rather than a single “magic bullet.”The inevitable varia-
tion in patient response to any specific agent is another factor driving the
need for a full spectrum of therapeutic options.
This compendium also offers a valuable perspective on some of the chal-
lenges inherent in identification and clinical testing of new molecular entities
for neurodegenerative diseases.One of the biggest hurdles is the reality of the
drug development timeline. A typical estimate for the time needed to move
from target identification and validation to new drug approval is 12–15 years.
The world’s rapidly changing demographics demonstrate clearly that time is
not on our side.We need to redouble our efforts to sustain the recent pace of
identification of promising new targets and to move every promising
approach from the laboratory into clinical testing as quickly as possible.
Validation of the first disease-modifying compounds will provide a highly
motivating proof of concept,and help us expand our horizons to make pre-
vention part of our conceptual framework for the ideal therapeutic land-
scape. Another important factor in shifting our priorities to prevention will
be the availability of interventions with a safety profile appropriate for use in
presymptomatic individuals.Preventing or delaying emergence of symptoms
may well be our ultimate therapeutic response to Alzheimer’s. As
Brookmeyer and colleagues concluded in 1998,delaying onset of Alzheimer’s
by even 5 years could decrease the prevalence of the disease by 50% over 50
years.The elegant and exciting strategies described here offer potentially vital
steps toward our goal of a world without Alzheimer’s disease.
William H.Thies,PhD
Vice President,
Medical and Scientific Relations
Alzheimer’s Association
Forewords vii
Another volume dealing with the neurobiology of Alzheimer’s disease might
seem superfluous,considering the attention that has been given to this disor-
der in recent years.Yet,this book provides something new:a highly desirable
collection of papers that describe the large variety of attempts at treatment,
based on clinical or pathological analysis. We have an evaluation of experi-
ence with many targets.The disappearance of much of the acetylcholine from
certain brain centers in Alzheimer’s disease keeps anticholinesterases in the
limelight.But there are other specific targets including muscarinic receptors,
glutamate receptors, apolipoprotein E, and other proteins known to play
some role in the aging process. Some investigators focus on immunological
processes;others look for means of overcoming destructive oxidant reactions
that occur in the brain,the downside of our oxygen-dependent lives.
The point is that basic research into cerebral processes is guiding the
attempts at therapy. One is reminded of the success attained by laboratory
studies in the treatment of another devastating disease of the nervous system,
namely,Parkinson disease.In that case,one clue from laboratory research led
to another,and ultimately to the introduction of L-DOPA (3,4-dihydroxy-L-
phenylalanine) as a specific therapeutic agent, followed by the discovery of
substitutes for this amino acid,i.e.,the various dopamine agonists.Without
minimizing the effort required to achieve a corresponding desirable result in
the case of Alzheimer’s disease, this analogy is presented as encouragement
to investigators of the aging brain.
The approach or approaches that will ultimately prevail in the successful
attack on Alzheimer’s disease is unpredictable. But the contributions in this
volume,as they focus attention on potential therapies,can be expected to aid
significantly in finding means to overcome a disease that at present takes such
a toll of individuals and of society.
Theodore L.Sourkes,OC,PhD,DU (h.c.),FRSC
Professor Emeritus
Departments of Psychiatry,Biochemistry,
and Pharmacology and Therapeutics
McGill University,Montreal,Quebec,Canada
Preface from the Editor
Alzheimer’s disease is a serious health concern in developed countries where
the population is progressively aging. At the personal level, the diagnosis of
the disease represents a devastating scenario for both the sufferer and the
caregivers. In recent years, medications have been developed that mitigate
somewhat the symptoms and delay,for a while,the progression of the disease.
It is expected that in the coming years new medications will be developed that
are capable of halting the chain of pathological events and symptoms of the
disease. This book covers a wide range of the pharmacological mechanisms
underlying the present and potential new therapies.The recent extraordinary
advances in our understanding of the cell and molecular biology of
Alzheimer’s disease allow for an optimistic forecast of innovative therapies.I
am glad that Andrea Malacuso, from Springer, asked me to edit a book
addressing these issues. The opportunity allows me to contribute a little to
the awareness of the pharmacological challenges.I am most grateful to all the
contributors who enthusiastically responded to the call. I am particularly
gratified in having them as authors of comprehensive reviews as they have
made important contributions to the field and,just as important,because of
their friendship,which I have had the privilege of enjoying for many years.
I trust that this book will be of value to a wide audience interested in cel-
lular and molecular mechanisms leading to the pathology of Alzheimer’s dis-
ease and on the multiple,possible,therapeutic opportunities ahead of us.The
field of research is enormous,and therefore we have selected the therapeutic
targets that seem the most hopeful and for which there is a solid rationale.
There are a number of emerging therapeutic targets, such as the inactiva-
tion/removal of Aβ peptides, among others, which might have potential
applications if specific leading compounds were to be identified.
On a personal note I would like to say how committed I am to this subject
of research,both because of its social importance and for the good science it
is generating.I would also like to thank all my past and present collaborators
and express my gratitude for the friendship of many of the leading actors in
this field. I would like to say here also “thank you”to Dr. Alan Frosst and
ix
x Preface from the Editor
the Frosst family and Merck-Frosst Canada for their interest in our work and
the granting institutions which make it possible, the Canadian Institutes of
Health Research, and the US Alzheimer’s Association. Finally, I would like
to say “thank you” to Martha, my wife and best friend, for her love and
fortitude, and to my daughters, Paula and Karina, for bringing us so much
happiness,and also for their patient ears to “Papa’s dreams.”
A.Claudio Cuello
Contents
FOREWORDS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
William H.Thies
Theodore L.Sourkes
PREFACE FROM THE EDITOR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
A.Claudio Cuello
LIST OF CONTRIBUTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
1. OVERVIEW OF THE ALZHEIMER’S DISEASE PATHOLOGY
AND POTENTIAL THERAPEUTIC TARGETS . . . . . . . . . . . . . 1
A.Claudio Cuello
2. TRIAL DESIGNS AND OUTCOMES TO MONITOR NOVEL
THERAPEUTICS IN ALZHEIMER’S DISEASE . . . . . . . . . . . . 28
Serge Gauthier
3. THE PHARMACOLOGICAL TREATMENT OF ALZHEIMER’S
DISEASE WITH CHOLINESTERASE INHIBITORS
AND MEMANTINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Gordon Keith Wilcock
4. M1 MUSCARINIC AGONISTS: A COMPREHENSIVE
THERAPY AGAINST MAJOR HALLMARKS OF
ALZHEIMER’S DISEASE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Abraham Fisher
5. CHOLINERGIC NEURODEGENERATION IN ALZHEIMER’S
DISEASE:BASIS FOR NERVE GROWTH FACTOR
THERAPY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Ahmad Salehi,Alexander Kleshevnikov,and William C.Mobley
xi