Mutagenesis by environmental pollutants and biomonitoring of environmental mutagens

Current Alzheimer Research (www.bentham.org/car), 2004, 1
Bentham Science Publishers Ltd.(www.bentham.org)

Preface

Unraveling Nature’s Secrets, from Neurons and Memory to Brain Disorders: Exploring the New Frontier of Alzheimer’s Disease

Debomoy K. Lahiri*

Departments of Psychiatry and of Medical and Molecular Genetics, Institute of Psychiatric Research, 791 Union Drive, Indiana University School of Medicine, Indianapolis, Indiana-46202, USA

We are passing through a golden era of biomedical research, witnessing firsthand the revolution caused by cloning, the human genome project, and recombinant DNA technology. Now barriers are diminishing: biochemistry, cellular/molecular biology, genetics, and computer technology are all merging together to tackle a biological phenomenon from the evolutionary angle, a biologist’s quest to unravel the secret of nature, such as normal brain function, but also to study its aberration, a diseased state. The current reductionist approach of studying the structure and function of genes and proteins involved in a biological process complements the holistic approach of physiology and brain imaging, and this dual approach is the hallmark of this golden era of biomedical research. Studying nature’s secret and understanding the normal pathway is one part of the research, to put it poetically: “[S]he is vanity of vanities; but not to us, to whom she has made herself of the greatest importance. She allows every child to play tricks with her; every fool to have judgment upon her; thousands to walk stupidly over her and see nothing; and takes her pleasure and finds her account in them all. We obey her laws even when we rebel against them; we work with her even when we desire to work against her”[1]. Another part of research is to decipher nature’s other secret, the “abnormal pathway.” I can borrow the aphorisms by Goethe as said in another context: “[S]he is rough and tender… She is cunning, but for good ends; and it is best not to notice her tricks. She is complete, but never finished. As she works now, so can she always work. Everyone sees her in his own fashion. She hides under a thousand names and phrases…”[1]. Studying nature’s “normal” and “abnormal” pathways using the basic and clinical research tools forms the pillar of modern biomedical science, and will be the major theme of a new journal. As T. H. Huxley wrote in 1869, “It seemed to me that no more fitting preface could be put before a Journal, which aims to mirror the progress of that fashioning by Nature of a picture of herself, in the mind of man, which we call the progress of Science”[1].

Neuroscience is not a bystander in this biomedical progress, but rather an active participant in the current revolution of “molecular medicine”[2]. This has fundamentally changed our thinking about human disease, which is no longer considered simply a “clinicopathological entity,” but a product of a cascade of biochemical events with a defined beginning that could in some cases be “predictable.” For example, contrary to long-held dogma, the adult brain is no longer considered to be rigid “hardware,” but rather, significantly more “plastic” or flexible than anyone thought [2]. This observation has far-reaching implications in brain disorders such as Alzheimer’s disease (AD). The use of molecular tools to dissect and then assemble different biochemical pathways involved in the central nervous system gave birth to disciplines such as molecular neuroscience and biological psychiatry.

We have witnessed the impressive growth of the neuroscience research community over the last decade worldwide. Though biomedical science is flourishing, the puzzles of brain disorders have yet not been fully solved nor their cures found. What Alois Alzheimer [3] found troublesome in the brains of his patients in 1906, such as the presence of “plaques,” still affects over 4 million individuals in the United States and 10 million more worldwide [4]. Our challenge is to continue research to determine its cause, and ultimately to find its prevention and cure. But the news is not that bad. What Alzheimer observed in his patients has served as a good starting point, a relevant paradigm to study and mimic the disease in various clinical and animal models, and yes, there are five FDA-approved drugs to treat some subjects with mild to moderate AD [4]. The fundamental problem in AD is the loss of memory, cognition, attention, orientation, and logic, along with associated behavioral symptoms. It is more than the modification of synaptic strengths, which are central to the formation and storage of memories.

The etiology of AD is still a mystery. Although age is primarily a risk factor for developing the disorder, AD is certainly a mutifactorial disease. The emerging picture is that AD is a genetically complex and heterogeneous disorder, that is to say, several biologically distinct disorders may exist that because of our limited knowledge are today all grouped together as AD. In simple terms, AD seems to result from a series of poorly understood steps in a pathogenic pathway that leads to the formation of amyloid deposits or “neuritic plaques,” which are chemical deposits consisting of degenerating nerve cells combined mostly with a form of protein called amyloid b (Ab). This small potentially toxic protein is produced from a large b–amyloid precursor protein (APP) by enzymes collectively called “secretase.” Another major histological feature of AD is the formation of neurofibrillary tangles, which are malformations within nerve cells combined with hyperphoshorylated tau proteins. AD patients exhibit these plaques and tangles in the autopsied brain. AD is also associated with a severe loss of cholinergic neurons in the brain, which leads to decreased levels of the neurotransmitter acetylcholine. However, controversy continues regarding whether the plaques and tangles that characterize AD are the cause or consequence of AD.

Several interesting new research discoveries have recently been made on key proteins and pathways involved in AD, with emphasis on new therapeutic strategies. The AD field is currently highlighted by the development of novel inhibitors for secretase enzymes, including BACE, and tau phosphorylation as targets for the treatment of AD. Studies on the apolipoprotein E, beta-amyloid protein metabolism, and neurodegeneration, and their implications for AD therapies are important. At the clinical level, studies on anti-amyloid drugs, metal chelators, NMDA antagonists, neurotrophic factors, statins and immunotherapy for AD would be promising. Other novel avenues include anti-inflammatory agents, antioxidants, cholesterol-lowering agents, hormone therapy, and a vaccination strategy for treating or slowing the progression of AD. There has been a remarkable advance in understanding the function of cholinesterase, both acetyl and butyryl, in the brain and the use of muscarinic agonists, nicotinic agents, and novel cholinesterase inhibitors, such as phenserine, in AD. The current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in AD in order to effectively diagnose the illness and prevent its occurrence. The results of clinical trials for drugs based on the aforementioned research are eagerly awaited. There is also a need to develop early potential diagnostic tools, such as brain imaging; new quantitative markers will be critical to better follow the course of the disease and to evaluate different therapeutic strategies.

Our knowledge and understanding of AD continues to grow at an unprecedented rate. A quick survey of the PubMed database reveals a continuing explosion of research in different areas of AD, from biochemical, epidemiological, genetic, and molecular research to clinical levels. A simple search of “Alzheimer’s disease” in Medline reveals over 38,000 citations. Notably, translation research is progressing very rapidly, as is evident from several ongoing “clinical trials” that are now at various phases of development. This advancement in the AD research engine is primarily driven by researchers from all over the world who cut across the disciplines. Research work that bridges the gap between basic science discovery and clinical studies becomes extremely important for the development of new therapeutic regimens.

It is now necessary for researchers and educators to integrate different branches of AD research in order to communicate major research findings effectively to clinicians, neuroscientists, health science professionals, grant administrators, and policy makers. Presently, there are only a few journals devoted to the different aspects of AD research. To bridge this gap, Bentham Science Publishers has decided to launch a new journal entitled Current Alzheimer Research, beginning with this issue (February 2004). Current Alzheimer Research will publish cutting-edge reviews and original research papers on all aspects of AD. This international journal will not only advance the field but also effectively complement the existing excellent journals related to neuroscience and AD.

Current Alzheimer Research plans to cover a breadth of topics for an audience of both basic neuroscientists and clinicians. The journal will provide a platform for the critical review of research, and also original reports that address disease mechanisms at the biochemical, genetic, and molecular levels. The journal will serve as an international forum for the publication of topic reviews, original research, and translational research on different aspects of Alzheimer’s disease; there will be an emphasis on novel therapeutic strategies for this devastating disorder.

These are just some examples of current trends and predictions in AD research. We will discuss, debate, and challenge some of these aspects in the pages of Current Alzheimer Research only to find out, to our surprise, that certain widely held theories may not pass the test of time. How can we effectively monitor the progress of research on AD? What are the guidelines? I quote the rules laid down over 120 years ago in the inaugural issue of the journal Science [5]: “Science must be true to itself as well as in accord with its surroundings. It must maintain ever the highest tone and the most impartial accuracy. It must covet the scrutiny of every eye, and must be generous ever in the acknowledgment of its shortcomings. Higher than all, it must be devoted to the truth. It must cheerfully undertake the severest labor to secure it, and must deem no sacrifice too great in order to preserve it. It must have an unlimited capacity for work, and an unlimited enthusiasm in it, while at the same time a proper reserve in affirming the results of it. While striving itself for the highest attainable accuracy, it must be catholic and liberal toward others. It must not magnify differences, nor impute motives.”

AD research, like all science, thrives on serendipity and unexpected discovery, and we hope that Current Alzheimer Research will witness and report some of those moments of unveiling nature’s secrets. For this “it must be ready to adjust, with the utmost patience, conclusions which are apparently discordant. It must treat all questions with fairness and candor. When it ventures nearest the boundaries of knowledge, it should assert itself cautiously. In its relations with other departments of knowledge, it must preserve toward them a due consideration. It must venture upon prediction with circumspection. It must take care, on the one hand, not to set too narrow limits to the possibilities of discovery; on the other, it must be quick to discern the directions of advance; and to utilize the smallest suggestion to promote discovery. It must be fruitful in working hypotheses, but it must test these with unsparing rigor before it offers them as a part of established truth”[5].

Research is supposed to create new knowledge, and similarly AD research will open up new fronts that will be equally important for other life science disciplines also. In this context Current Alzheimer Research will support the view expressed some time ago: “... in order that it may advance beyond the boundaries of present knowledge, it must keep fully and constantly informed of the position of the ever-varying line which marks the limits of the known. It must have and use all the publications in which are recorded the work done by others in all the various fields of research. It must not waste its energies in doing again what has already been well done. Beginning its work where others have left off, it must carry out into the misty region of hypothesis the most complete methods known for the solution of the problems it has attacked. Not contented alone with receiving the work of others, it must furnish its methods and results, for publication, thus contributing its part to the interchange and discussion of opinions by which discoveries finally become an integral part of truth. It must recognize the importance of making the scientific literature of the day the repository of scientific progress; so that every advance, whether of theoretic or applied science, may find a record in its pages” [5].

In short, Current Alzheimer Research is meant to disseminate up-to-date knowledge in different aspects of current AD research from world-renowned experts. This is more so because Current Alzheimer Research is one of the few journals exclusively devoted to AD. During its early development, Current Alzheimer Research has garnered the support of well-recognized investigators and lists a highly respected international editorial board. As a result, the journal promises to become one of the essential resources for new and exciting developments in the field of AD research. This new journal has an educational mission as well: to educate persons other than elite AD researchers about the neurobiology of AD. Current Alzheimer Research is a new vehicle to disseminate the advances in AD research to another audience group, such as patients, healthcare providers and science policy administrators.

This is still a “work in progress,” so I would like readers’ comments, advice, and suggestions to improve this journal. As you can see in the contents for the first issue of Current Alzheimer Research, it is a mixed bag of both basic and clinical sciences. It represents a wide variety of research areas: cell biology (protein trafficking), cross-cultural studies, genetics, neuropharmacology (neurotransmitters), oxidative stress, and cognitive event-related potentials. Likewise, it covers amyloid, apoE, specific kinases (cdK5), tangles, tau, neurodegneration, synaptic transmission, and neuroscience’s perspective in relation to AD (preface).

Current Alzheimer Research is a new vehicle and is run by AD researchers worldwide across a wide range of disciplines. It is fueled by our incessant quest for new knowledge to find out the secrets of nature and then utilize them for the benefit of mankind, in this case how to prevent and ultimately cure a devastating disease such as AD. With great humility and honor I take the responsibility as editor-in-chief of Current Alzheimer Research. I deeply appreciate the excellent cooperation from the Regional Editors, Associate Editors, and other members of the Editorial Advisory Board of the journal. I am grateful to Bentham Science Publishers for their constant support and advice. I also thank Indiana University School of Medicine. Personally, I am enormously indebted to my late father, who enlightened and guided me through the path of knowledge and ignited in me the curiosity for studying the mystery of brain and mind.

The year 2004 opens with hope and optimism in the AD research community due to its great challenges and opportunities. What was said in 1883 is true again: “[T]he scientific sky is clear, and the outlook quite promising. If we follow a course true to itself and to its surroundings, … science has nothing to fear from the future.” With excellent scientific resources and the hope of increasing public and private support for AD research, Current Alzheimer Research embarks upon a bright future. May this journal succeed by recognizing the progress in AD research and by changing and adapting to new challenges; at this moment, please join me in helping it forward.

References

[1] Huxley TH. Nature: Aphorisms by Goethe. Nature 1(1): 9–11 (1869).

[2] Culliton B. Molecular medicine in a changing world. Nature Med 1(1): 1 (1995).

[3] Alzheimer A. Über eine eigenartige Erkangung der Hirnrinde. All Z Psychiatr Psych Gerichtl Med 64: 146–148 (1907). An English translation: Clin Anat 8(6): 429-431 (1995)

[4] Alzheimer’s Association, Chicago, IL: web site http://www.alz.org/.

[5] King, M. Future of American Science. Science 1(1): 1–3 (1883).