About the Book
Preface:
To understand Alzheimera (TM)s disease (AD) is one of the major thrusts of present-day clinical research, strongly supported by more fundamental cellular, biochemical, immunological and structural studies. It is these latter that receive attention within this book. This compilation of 20 chapters indicates the diversity of work currently in progress and summarizes the current state of knowledge. Experienced authors who are scientifically active in their fields of study have been selected as contributors to this book, in an attempt to present a reasonably complete survey of the field. Inevitably, some exciting topics for one reason or another have not been included, for which we can only apologize.
Standardization of terminology is often a problem in science, not least in the Alzheimer field; editorial effort has been made to achieve standardazation between the Chapters, but some minor yet acceptable personal / author variation is still present, i.e. A-amyloid/amyloid-A; AA42/AA1-42/AA1-42!
The book commences with a broad survey of the contribution that the range of available microscopical techniques has made to the study of Alzheimera (TM)s amyloid plaques and amyloid fibrillogenesis. This chapter also serves as an Introduction to the book, since several of the topics introduced here are expanded upon in later chapters. Also, it is significant to the presence of this chapter that the initial discovery of brain plaques, by Alois Alzheimer, utilized light microscopy, a technique that continues to be extremely valuable in present-day AD research. Then follow 19 further chapters dealing with interesting areas of research that have a bearing upon Alzheimera (TM)sdisease. The authors present their own data within the context of a review of related work from others in their field of study.
Transgenic mouse models for AD are increasingly important and widely used, as is the understanding of the enzymology and biochemistry of amyloid A production from the amyloid precursor protein (APP) by the A- and g -secretases, and the non-amyloidogenic APP cleavage products due to a -secreatases. Similarly, discussion of the enzymes responsible for the natural degradation of amyloid-A is included. Oxidative stress in AD and the possible protective role of vitamin E have emerged as highly significant topics. Likewise, the role of the metals, aluminium copper and zinc in AD is thoroughly addressed, along with the possible value of metal chelation. Current concepts as to the fundamental importance of amyloid-A oligomers versus AA fibrillar deposits (diffuse and senile plaques) in the pathogenesis of AD is presented, along with the likely role of tissue and cellular cholesterol in the promotion of AA fibrillogenesis, and Congo red binding to AA fibrils.
Several naturally occurring human proteins have the ability to bind to AA and are found in AD diffuse and senile plaques. Apolipoprotein E4, clusterin (ApoJ) and acetylcholinesterase are considered in depth. The direct effects of AA on neuronal membranes, in terms of neuronal membrane fluidity changes and calcium ion transport are dealt with, then the role of amyloid inhibitors and A-sheet breaking drugs is included. The likely important beneficial effects of the cholesterol-lowering drugs, the statins, in lowering brain AA and consequently the therapeutic prevention of AD by reducing AA deposition in plaquesis discussed thoroughly. Finally, an exciting new concept is advanced, namely the possible significance of phosphorylated AA in Alzheimera (TM)s disease. From in vitro experiments AA phosphorylation appears to increase the proportion of AA oligomeric forms, an observation which correlates with a the higher cytotoxicity of this species, compared to non-phosphorylated AA.
The editors hope that this book will be of interest and value to both medical and scientific research communities working on AD, and to others with a more general interest in the understanding of this devastating neurodegenerative disorder of the elderly.
Prof. J. Robin Harris
Prof. Falk Fahrenholz
University of Mainz
August, 2004
This book contains a survey of present-day research into the biomedical fundamentals of Alzheimer 's disease (AD). It contains 20 chapters dealing with widely ranging topics, all of which have a bearing upon the understanding and treatment of AD. Starting with a broad survey of the contribution that the various microscopical techniques (light microscopy, electron microscopy, atomic force microscopy) have made since the seminal light microscopical studies of Alois Alzheimer, the book presents chapters on specialist topics: transgenic mouse models of AD; the enzymology of amyloid- production and degradation; oxidant stress and antioxidant protection; the involvement of metal ions and the influence of chelators; the importance of amyloid- oligomers and fibrils, the role of cholesterol in their formation and characteristic binding of the dye Congo red; of the many AD plaque-associated proteins, ApoE4, clusterin and acetylcholinesterase receive individual attention; the effect of amyloid- on neuronal membrane calcium channels and membrane fluidity are covered, as are drug interactions, the -sheet breaking peptides and the statins that may prevent oligomer/fibril formation in AD; the possible significance of amyloid- phosphorylation receives detailed attention.
Overall, the book contains a broad range of current information on cellular, biochemical and structural aspects of amyloid-, of direct relevance to Alzheimer 's disease.