Brain, Vol. 124, No. 7, 1467-1468,
July 2001
© 2001 Oxford University Press
Book reviews |
MOLECULAR MECHANISMS OF NEURODEGENERATIVE DISEASES.
By Marie-Francoise Chesselet. 2000. Totowa: Humana Press. Price $125.00. Pp. 410. ISBN 0-89603-804-1.
Department of Neurology, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
The development of cellular and animal models of neurodegenerative disease has fuelled research into the basic mechanisms of neurodegeneration over the last decade. The profusion of original papers covering this topic reflects these advances. A Medline search between 1980 and 1990 identified 500 original articles specifically addressing the mechanisms of neurodegeneration, but in a similar time period between 1990 and March 2001, the number increased 10-fold to over 5500. As the editor of Molecular Mechanisms of Neurodegenerative Diseases points out, a comprehensive review of the literature would require much more than the 500 folio pages in this book, so there has to be a compromise. There are two ways around the problem of writing a short book on a large topic. One is to focus on common mechanisms, illustrating our understanding of these mechanisms by referring to specific disease entities. The other is to focus on a collection of specific disorders and hope that this covers the most important areas. This book takes the latter approach: it is disease-based, rather than mechanism-based. This has the advantage that, by and large, each chapter deals with the subject matter in satisfactory detail. Unfortunately, its major disadvantage is that after reading the whole book, the reader is not left with an overview of our contemporary understanding of common cellular mechanisms in neurodegenerative disease. There are some glaring examples of the deficiencies: despite its importance, apoptosis (programmed cell death) is only considered superficially in different chapters. Similarly, second messenger systems, calcium signalling, free-radicals and excitotoxicity are not specifically covered, and the chapter on mitochondrial mechanisms in Parkinson's disease presents a somewhat polar and contentious view on one small aspect of mitochondria and neurodegeneration. There are, however, notable exceptions. The chapter on proteolytic mechanisms in neurodegenerative disease successfully bridges the gap, discussing the role of this basic mechanism in diverse disease states. Similarly, the chapter on tau and 
-synuclein discusses the role of these proteins in a range of different disorders. Finally, the chapter on dopamine and its role in promoting cell death is discussed with relevance to a broad range of neurodegenerative diseases.
The book focuses on three main areas: Alzheimer's disease, Parkinson's disease and trinucleotide repeat disorders (SCA1, SCA3, Kennedy's disease and Huntington's disease). The strongest section deals with disease mechanisms in Alzheimer's disease, and takes up nearly 40% of the text. The ß-amyloid (Aß) hypothesis is now over a decade old, and new evidence supporting the original hypothesis, gained through the study of cellular and animal models, is convincingly presented. There is a succinct chapter summarizing studies of genetically engineered mice with altered expression of Aß, amyloid precursor protein, presenilin and apolipoprotein E, but as the authors conclude, although these mice show pathological features of Alzheimer's disease, they lack behavioural features, which are an essential prerequisite for future studies with potential disease-modifying drugs and vaccines. In the subsequent chapters, the emerging interest in the role of glial cells in pathogenesis of Alzheimer's disease and inflammatory mechanisms involved in Alzheimer's disease are appropriately considered in some detail. This is important given the results of recent animal and clinical studies using non-steroidal anti-inflammatory drugs. Perhaps the most refreshing aspect of this book is the way that the different mechanisms are presented in such a way as to highlight new strategies for the treatment of neurodegenerative disorders, not just as glib references to treatment aims, but as solid hypotheses based on specific agents which may be tested in the future on animal models. There is a fascinating chapter on the huge number of potential treatment strategies for Alzheimer's disease. This is written by scientists working at Bristol-Myers Squibb and, although in parts it reads like a well-referenced list, it illustrates the broad range of possible approaches currently being studied. The authors conclude that, given the crucial role that Aß pays in disease pathogenesis, strategies designed to reduce ß-amyloid have the greatest therapeutic potential. I would have liked to see greater reference to recent studies using Aß vaccines in the various transgenic mouse models of Alzheimer's disease, and recent developments with ß and 
secretase inhibitors, but unfortunately I suspect that many of these studies were published after this book went to press.
There are two chapters on disease mechanisms in spinocerebellar ataxia (SCA1 and SCA3), one on spinobulbar muscular atrophy (Kennedy's disease) and one on mouse models in Huntington's disease. Whilst each chapter reads well, and deals with the clinical genetics, cellular models and mouse models of each disorder, they somehow seem disconnected. This is disappointing, given some of the similarities involved in the cellular pathogenesis of these triplet repeat disorders. There is also a chapter on PET. This is well written and covers the application of PET to a broad range of disorders, but it could be argued that this topic is out of place in a book that largely focuses on the laboratory science of neurodegeneration. This overview may, of course, be welcomed by many readers with little or no experience of these techniques.
The book ends with a discussion of disease models using the fruit fly. This is an interesting and amusing read. For example, how many of us were aware that the `eggroll' mutant drosophila bears similarities to Tay-Sachs disease; and that the `bubblegum' strain has a mutation in the very long chain fatty acids CoA sythetase gene homologue and mimics adrenoleukodystrophy? Interestingly, the neurodegeneration which occurs in `bubblegum' can be prevented by feeding the flies glyceryl triolate, which is a component of Lorenzo's oil. Other mutant strains include `Swiss cheese', `sponge cake' and the rather unfortunate `drop dead' variety! These mutants share pathological features with a range of neurodegenerative disorders, and may be of use in teasing out common cellular mechanisms of disease.
In conclusion, this book is generally up to date and well written, with an optimistic and constructive perspective on the development of new treatments. Unfortunately, the book is too short to serve as a reference for a laboratory scientist working in a rapidly evolving field, and yet too `molecular' for a Neurologist primarily interested in the clinical aspects of neurodegenerative disease. The chapters on Alzheimer's disease form the strongest section, and would serve as an excellent introduction or refresher course for those contemplating molecular research in this area. Unfortunately, other parts seem like a series of somewhat disconnected reviews, and there are significant deficiencies for some important basic mechanisms. Whilst I would recommend this book for a university library, I am not sure it has a place on a personal bookshelf.
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