Research and Perspectives in Alzheimer's Disease – serie

Recent advances in understanding the role of protein dysmetabolism in neurodegeneration was the theme of the Fondation IPSEN meeting addressing Genotype-Proteotype-Phenotype relationships. Experts from international laboratories contributed to the  current volume to produce a comprehensive overview of the role of protein misfolding in neurodegeneration. Links between genotype and protein characteristics and between proteotype and clinical phenomenology were discussed across diseases categories. Progress in understanding the role of abnormalities of protein metabolism may lead to the identification of biological markers relevant to disease monitoring and to the development of new therapeutic agents capable of modifying and ameliorating basic neurodegenerative mechanisms.

Few medical or scientific addresses have so unmistakeably made history as the presentation delivered by Alois Alzheimer on November 4, 1906 in Tübingen. The celebratory event, "Alzheimer 100 Years and Beyond" organized on the initiation of the Alzheimer community in Germany and worldwide, in collaboration with the Fondation Ipsen, was the highlight of the Year of Alzheimer. However, beyond these few months of tributes, the centennial offers a unique opportunity to assess both the progress achieved and the uncertainties remaining. This volume, a collection comprised mainly of articles by the invited speakers and also of a few other prominent researchers, is meant to be a record of those events.

Fondation Ipsen sponsored a meeting in Paris in February 2000 on the emerging paradigm-shift in our understanding of the major degenerative diseases which- affect the aging human brain. This book sumarizes our deliberations on some of these major neurodegenerative diseases that are characterized by protein depos- its, and that are due to the pathogenic gain of function of an otherwise normal neuronal protein. For each of the major human neurodegenerative diseases covered in this book -the most prominent being Alzheimer's disease -experimental models are described, including cell culture systems and animal models which range from the round worm, Caenorhabditis elegans, the fruitfly, Drosophila melanogaster, to rodents. Remarkably, in the sporadic forms of these human diseases, only a minor change in the level of production or turn-over of the relevant proteins is sufficient to cause disease in late adult-hood. Neurodegeneration in Alzheimer's disease, for example, usually results in symptoms and signs in the seventh to eighth decades.In contrast, the development of protein deposits in transgenic mice over-expressing the corresponding disease gene parallels the genetic forms of the human diseases in regard to its manifestation occuring half-way through its normal life-span, i. e. about 50 years in humans (the so-called "presenium") and 9 to 12 months in the mouse. Nevertheless, these models have served to elu- cidate many of the pathways underlying the human disease processes, for instance clarifying the neuronal origin of parenchymal and perivascular amyloid in Alzheimer's disease and Creutzfeldt-Jakob disease.

Can molecular mechanisms involved in neural development help us to understand, prevent and perhaps reverse the course of brain ageing and neurodegenerative disorders? Brain development and function require complex cellular and molecular processes controlled by a number of different signaling mechanisms. One such signaling mechanism, the Notch pathway, has been recognized as an important player in the regulation of cellfate decisions during early neural development. However, the action of this evolutionary conserved and widely used cell-cell interaction mechanism is not confined to the developing nervous system. In addition, recent studies have shown that elucidating the mechanism of Notch signaling and its role in the brain is important for our understanding of neurological disorders such as Alzheimer's disease and cerebral arteriopathy CADASIL.

In this volume are contributions based on a meeting arranged by the WHO and the Fondation IPSEN. The scientists focus on neurodegenerative disorders like Alzheimer's Disease, Chromosome 17-Linked Dementia, Parkinson's Disease and disorders with tauopathies.

In disorders like Huntington’s disease, amyotrophic lateral sclerosis and even Parkinson’s disease, unbiased genetic screens, linkage analysis and positional cloning have identified causative genes that subsequently allowed the formulation of specific biochemical hypotheses.

Neurodegenerative disorders are common and devastating. Rationally, the most effective treatments will target pathogenetic mechanisms. While alternative - proaches, based on alleviating the symptoms of patients with Alzheimer disease, Parkinson disease, Huntington disease, prion disorders or amyotrophic lateral sc- rosis, can be expected to reduce suffering, studies of pathogenesis of these a- related disorders will be most important for enabling early diagnosis and the creation of preventative and curative treatments. It is in this context that a recent IPSEN rd meeting (The 23 Colloque Medecine ' et Recherche, April 28, 2008) focused on a role for disruption of intracellular traf?cking in neurodegenerative disorders. The meeting captured emerging insights into pathogenesis from disrupted traf?cking and processing of proteins implicated in age-related degeneration. Protein folding, traf?cking and signaling were the principal topics covered at the meeting. Importantly, the presenters pointed to the importantly intersection of these themes. While the proteolytic processing of APP into its toxic product, the A? peptide, is an intensive focus of work in many laboratories, it is only relatively recently that investigators have begun to examine in depth the cellular compartments and traf?cking events that mediate APP processing and how derangement of tr- ?cking pathways could impact them.

The central nervous system controls vital functions by ef?ciently coordinating peripheral and central cascades of signals and networks in an orchestrated manner. Historically, the brain was considered to be insulin independent. These earlier views have been challenged by ?ndings demonstrating that insulin exerts multiple actions in the brain, regulating vital biological processes such as life span, neuronal survival, cognition, reproduction, feeding behavior, energy balance, and glucose and fat metabolism, and that inef?cient central action of insulin contributes to the development of severe pathologies (Banks et al. 2000; Gerozissis 2003, 2004, 2008; Lustman and Clouse 2005; Okamoto et al. 2001; Park 2002; Perrin et al. 2004; Pocai et al. 2005; Reger et al. 2008; Schwartz and Porte, 2005; Schubert et al. 2004; van der Heide et al. 2005; Woods et al. 1979; Wrighten et al. 2008). Insulin and speci?c insulin receptors are widely distributed in the networks of the central nervous system related mainly to feeding or cognition (Baskin et al. 1983; Bruning et al. 2000; Gerozissis 2003, 2008; Havrankova et al. 1978a, b; Schechter et al. 1996; Schulingkamp et al. 2000; Schwartz et al.1992; Zhao et al. 2004). Insulin receptors located in the synapses of neurons and in astrocytes are present in high concentrations in the cerebral cortex, olfactory bulb, hippocampus, amygdala, cerebellum and hypothalamus (Abbott et al., 1999; Havrankova et al.

Recent advances in understanding the role of protein dysmetabolism in neurodegeneration was the theme of the Fondation IPSEN meeting addressing Genotype-Proteotype-Phenotype relationships. Experts from international laboratories contributed to the  current volume to produce a comprehensive overview of the role of protein misfolding in neurodegeneration. Links between genotype and protein characteristics and between proteotype and clinical phenomenology were discussed across diseases categories. Progress in understanding the role of abnormalities of protein metabolism may lead to the identification of biological markers relevant to disease monitoring and to the development of new therapeutic agents capable of modifying and ameliorating basic neurodegenerative mechanisms.

Few medical or scientific addresses have so unmistakeably made history as the presentation delivered by Alois Alzheimer on November 4, 1906 in Tübingen. The celebratory event, "Alzheimer 100 Years and Beyond" organized on the initiation of the Alzheimer community in Germany and worldwide, in collaboration with the Fondation Ipsen, was the highlight of the Year of Alzheimer. However, beyond these few months of tributes, the centennial offers a unique opportunity to assess both the progress achieved and the uncertainties remaining. This volume, a collection comprised mainly of articles by the invited speakers and also of a few other prominent researchers, is meant to be a record of those events.

Fondation Ipsen sponsored a meeting in Paris in February 2000 on the emerging paradigm-shift in our understanding of the major degenerative diseases which- affect the aging human brain. This book sumarizes our deliberations on some of these major neurodegenerative diseases that are characterized by protein depos- its, and that are due to the pathogenic gain of function of an otherwise normal neuronal protein. For each of the major human neurodegenerative diseases covered in this book -the most prominent being Alzheimer's disease -experimental models are described, including cell culture systems and animal models which range from the round worm, Caenorhabditis elegans, the fruitfly, Drosophila melanogaster, to rodents. Remarkably, in the sporadic forms of these human diseases, only a minor change in the level of production or turn-over of the relevant proteins is sufficient to cause disease in late adult-hood. Neurodegeneration in Alzheimer's disease, for example, usually results in symptoms and signs in the seventh to eighth decades.In contrast, the development of protein deposits in transgenic mice over-expressing the corresponding disease gene parallels the genetic forms of the human diseases in regard to its manifestation occuring half-way through its normal life-span, i. e. about 50 years in humans (the so-called "presenium") and 9 to 12 months in the mouse. Nevertheless, these models have served to elu- cidate many of the pathways underlying the human disease processes, for instance clarifying the neuronal origin of parenchymal and perivascular amyloid in Alzheimer's disease and Creutzfeldt-Jakob disease.

In this volume are contributions based on a meeting arranged by the WHO and the Fondation IPSEN. The scientists focus on neurodegenerative disorders like Alzheimer's Disease, Chromosome 17-Linked Dementia, Parkinson's Disease and disorders with tauopathies.

In disorders like Huntington’s disease, amyotrophic lateral sclerosis and even Parkinson’s disease, unbiased genetic screens, linkage analysis and positional cloning have identified causative genes that subsequently allowed the formulation of specific biochemical hypotheses.

Neurodegenerative disorders are common and devastating. Rationally, the most effective treatments will target pathogenetic mechanisms. While alternative - proaches, based on alleviating the symptoms of patients with Alzheimer disease, Parkinson disease, Huntington disease, prion disorders or amyotrophic lateral sc- rosis, can be expected to reduce suffering, studies of pathogenesis of these a- related disorders will be most important for enabling early diagnosis and the creation of preventative and curative treatments. It is in this context that a recent IPSEN rd meeting (The 23 Colloque Medecine ' et Recherche, April 28, 2008) focused on a role for disruption of intracellular traf?cking in neurodegenerative disorders. The meeting captured emerging insights into pathogenesis from disrupted traf?cking and processing of proteins implicated in age-related degeneration. Protein folding, traf?cking and signaling were the principal topics covered at the meeting. Importantly, the presenters pointed to the importantly intersection of these themes. While the proteolytic processing of APP into its toxic product, the A? peptide, is an intensive focus of work in many laboratories, it is only relatively recently that investigators have begun to examine in depth the cellular compartments and traf?cking events that mediate APP processing and how derangement of tr- ?cking pathways could impact them.

However, cancer and neurodegeneration represent yin-yang counterpoints in the regulation of cell growth, and it is reasonable to hypothesize that key regulatory events mediated by oncogenes and tumor suppressor genes in cancer may also affect neurodegenerative processes

The central nervous system controls vital functions by ef?ciently coordinating peripheral and central cascades of signals and networks in an orchestrated manner. Historically, the brain was considered to be insulin independent. These earlier views have been challenged by ?ndings demonstrating that insulin exerts multiple actions in the brain, regulating vital biological processes such as life span, neuronal survival, cognition, reproduction, feeding behavior, energy balance, and glucose and fat metabolism, and that inef?cient central action of insulin contributes to the development of severe pathologies (Banks et al. 2000; Gerozissis 2003, 2004, 2008; Lustman and Clouse 2005; Okamoto et al. 2001; Park 2002; Perrin et al. 2004; Pocai et al. 2005; Reger et al. 2008; Schwartz and Porte, 2005; Schubert et al. 2004; van der Heide et al. 2005; Woods et al. 1979; Wrighten et al. 2008). Insulin and speci?c insulin receptors are widely distributed in the networks of the central nervous system related mainly to feeding or cognition (Baskin et al. 1983; Bruning et al. 2000; Gerozissis 2003, 2008; Havrankova et al. 1978a, b; Schechter et al. 1996; Schulingkamp et al. 2000; Schwartz et al.1992; Zhao et al. 2004). Insulin receptors located in the synapses of neurons and in astrocytes are present in high concentrations in the cerebral cortex, olfactory bulb, hippocampus, amygdala, cerebellum and hypothalamus (Abbott et al., 1999; Havrankova et al.

However, cancer and neurodegeneration represent yin-yang counterpoints in the regulation of cell growth, and it is reasonable to hypothesize that key regulatory events mediated by oncogenes and tumor suppressor genes in cancer may also affect neurodegenerative processes

The health of the proteome depends upon protein quality control to regulate the proper synthesis, folding, translocation, and clearance of proteins. The cell is challenged constantly by environmental and physiological stress, aging, and the chronic expressions of disease associated misfolded proteins. Substantial evidence supports the hypothesis that the expression of damaged proteins initiates a cascade of molecular events that leads to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and other diseases of protein conformation.

The misfolding and aggregation of specific proteins is an early and obligatory event in many of the age-related neurodegenerative diseases of humans. The initial cause of this pathogenic cascade and the means whereby disease spreads through the nervous system, remain uncertain. A recent surge of research, first instigated by pathologic similarities between prion disease and Alzheimer’s disease, increasingly implicates the conversion of disease-specific proteins into an aggregate-prone b-sheet-rich state as the prime mover of the neurodegenerative process. This prion-like corruptive protein templating or seeding now characterizes such clinically and etiologically diverse neurological disorders as Alzheimer´s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. Understanding the misfolding, aggregation, trafficking and pathogenicity of the affected proteins could therefore reveal universal pathomechanistic principles for some of the most devastating and intractable human brain disorders. It is time to accept that the prion concept is no longer confined to prionoses but is a promising concept for the understanding and treatment of a remarkable variety of diseases that afflict primarily our aging society. ​

The misfolding and aggregation of specific proteins is an early and obligatory event in many of the age-related neurodegenerative diseases of humans. The initial cause of this pathogenic cascade and the means whereby disease spreads through the nervous system, remain uncertain. A recent surge of research, first instigated by pathologic similarities between prion disease and Alzheimer’s disease, increasingly implicates the conversion of disease-specific proteins into an aggregate-prone b-sheet-rich state as the prime mover of the neurodegenerative process. This prion-like corruptive protein templating or seeding now characterizes such clinically and etiologically diverse neurological disorders as Alzheimer´s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. Understanding the misfolding, aggregation, trafficking and pathogenicity of the affected proteins could therefore reveal universal pathomechanistic principles for some of the most devastating and intractable human brain disorders. It is time to accept that the prion concept is no longer confined to prionoses but is a promising concept for the understanding and treatment of a remarkable variety of diseases that afflict primarily our aging society. ​

The health of the proteome depends upon protein quality control to regulate the proper synthesis, folding, translocation, and clearance of proteins. The cell is challenged constantly by environmental and physiological stress, aging, and the chronic expressions of disease associated misfolded proteins. Substantial evidence supports the hypothesis that the expression of damaged proteins initiates a cascade of molecular events that leads to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and other diseases of protein conformation.

Alzheimer's disease is one of the major scientific, medical and social challenges of our time. This book, the first in the new series Research and Perspectives in Alzheimer's Disease, presents a particularly up-to-date approach of immunological and biochemical aspects. It is written by the most outstanding scientists and contains recent data. The following are among the most interesting ideas contained in this book: - Alzheimer's disease is a cerebral form of amyloidosis. - some data are in accordance with an immunological hypothesis of this disease. - degeneration of microvessels - including amyloid angiopathy - could be very important in the changes in the brain with Alzheimer's disease. - the molecular study of A4 protein and its precursor is important for the understanding of the disease. This synthesis by prominent scientists provides a stimulating hypothesis about the determinism of the disease.

This volume presents the proceedings of the symposium held in Toulouse on April 24, 1989, on the topic "Biological Markers of Alzheimer's Disease. " This sym­ posium was the fourth of a continuing and successful series of Colloques Medecine et Recherche organized by the Fondation IPSEN pour la Recherche Therapeutique, addressing various aspects of contemporary research in the field of Alzheimer's disease (AD). The series started in September 1987 with "Im­ munology and Alzheimer's Disease," followed 6 months later in Paris by "Gene­ tics and Alzheimer's Disease" and in September 1988 in Montpellier by "Neuronal Grafting and Alzheimer's Disease. " The present symposium was organized for the purpose of gathering the most current ideas concerning biological markers of AD. The papers presented at this symposium may be roughly subdivided into three groups. The first deals with the markers of AD at the level of the brain itself. These markers are studied either through the cerebrospinal fluid or through techniques such as nuclear magnetic resonance (NMR) - approaches which respectively aim at demonstrating the cerebral changes indicated by the debris resulting from the disease, or studying the possible neurochemical abnormalities that occur in the earlier stages of AD.

This volume contains the proceedings of the sixth Colloque M6decine et Re- cherche organized by the Fondation Ipsen pour la Recherche Therapeutique and devoted to Alzheimer's disease. It was held in Strasbourg on April 25, 1990 and dedicated to growth factors and Alzheimer's disease. The proceedings of the previous meetings were published as the present one in the same series: Immunology and Alzheimer's disease (A. Pouplard-Barthelaix, J. Emile, Y Christen eds., 1988), Genetics and Alzheimer's disease (P.-M. Sinet, Y Lamour, Y Christen eds., 1988), Neuronal grafting and Alzheimer's disease (F. Gage, A. Privat, Y Christen eds., 1989), Biological markers and Alzheimer's disease (F. Boller, R. Katzman, A. Rascol, J.-L. Signoret, Y Christen eds., 1989), Imaging, cerebral topography and Alzheimer's disease (S. I. Rapoport, H. Petit, D. Leys, Y Christen eds., 1990). The next meeting of the series entitled Neurophilosophy and Alzheimer's disease was being held in La Jolla (California, USA) on January 11,1991. The proceed- ings will be published this year. Yves Christen Fondation Ipsen Acknowledgements. The editors wish to express their gratitude to M. Sensenbren- ner (Strasbourg), A.Bjorklund (Lund), R. Terry (La Jolla) for their collaboration as chairmen for the meeting, G. Vincendon, dean of the Facult6 de M6decine de Strasbourg, who made the introductive talk, Mary Lynn Gage for her editorial assistance and Jacqueline Mervaillie for the organization of the meeting. Contents Neurotrophic Factors and Neurodegenerative Diseases F Hefti and B. Knusel ...

Any mention of the relationship, still poorly understood, between body (or brain) and mind invariably invokes the name of Descartes, who is often thought of as the father of modern philosophy and perhaps of neurophilosophy. Although a native of the heart of France (the region around Tours), Rene Descartes travelled widely, as everyone knows, especially to Holland and Sweden. It should come as no surprise, that the Congress of Neurophilosophy and Alzheimer's Disease was the first in the series of Fondation Ipsen Colloques Medecine et Recherche to be held outside France. The meeting was held in San Diego (California) on January 11, 1991. This venue was chosen for a number of reasons. The University of California San Diego is without doubt one of the most dynamic universities today. A good number of friends of the Fondation Ipsen who have taken part as speakers in previous conferences are based there. Patricia Churchland, whose publications have helped "launch" the term "neurophilosophy", also teaches there. The choice of this particular venue gave us the welcome opportunity of benefiting directly during the conference from the participation of many eminent (including some Nobel Prize-winning) scientists, including biochemists, neuro­ scientists and "alzheimerologist", psychologists, cognitive science specialists and philosophers.

This volume contains the proceedings of a symposium held in Marseille on April 6, 1992, on the topic "Heterogeneity of Alzheimer's disease. " This was the eighth of a continuing and very successful series of meetings related to Alzheimer's disease organized by the Fondation Ipsen pour la Recherche Therapeutique. These symposia, known as "Colloques medecine et recherche," started in 1987 and have dealt with widely different aspects of the disease such as immunology, genetics, neuronal grafting, biological markers, imaging, growth factors, and last year's less conventional topic of Neurophilo- sophy and Alzheimer's disease. The next IPSEN symposium dedicatet to Alz- heimer's disease will take place in Lyon on June 21, 1993, and will deal with "Amyloid protein precursors in development, aging, and alzheimer's disease. " It is being organized by Konrad Beyreuther, Colin Masters, Marc Trillet, and Yves Christen. Until a few years ago, several names were used to refer to the most common cause of dementia in the elderly. They included such terms as "senile psycho- sis," "organic brain syndrome," and "senile dementia." Following Kraepelin, the term "Alzheimer's disease" was often restricted to an uncommon condition starting at a younger age (before 60 or 65 years of age).

Alzheimer's disease is one of the major scientific, medical and social challenges of our time. This book (the third volume of proceedings of the Colloques Médecine et Recherche of the Fondation Ipsen pour la Recherche Thérapeutique) is dedicated to neuronal grafting and Alzheimer's disease. The wealth of basic information presented testifies to the progress that has been achieved in intracerebral grafting and to the utility of intracerebral grafting as a tool for the understanding of brain development, adult neuronal plasticity and age-related pathology. An answer to the question, whether neuronal grafting will be useful as a therapy for Alzheimer's disease, must wait for a better understanding of the disease and the identification of animal models that can be used to test potential therapies. Meanwhile, the tool of intracerebral grafting may, in the future, be used to address the pathophysiology of Alzheimer's disease.

Can molecular mechanisms involved in neural development help us to understand, prevent and perhaps reverse the course of brain ageing and neurodegenerative disorders? Brain development and function require complex cellular and molecular processes controlled by a number of different signaling mechanisms. One such signaling mechanism, the Notch pathway, has been recognized as an important player in the regulation of cellfate decisions during early neural development. However, the action of this evolutionary conserved and widely used cell-cell interaction mechanism is not confined to the developing nervous system. In addition, recent studies have shown that elucidating the mechanism of Notch signaling and its role in the brain is important for our understanding of neurological disorders such as Alzheimer's disease and cerebral arteriopathy CADASIL.

From large cross-sectional studies of autopsy material, it seems as if a time course of Alzheimer's Disease, at least on average, can be mapped out: a pattern of hierarchical vulnerability for neuronal loss and neurofibrillary tangles beginning in medial temporal lobe structures proceeding through association areas. Plaques follow their own temporal course, with widespread cortical deposits occurring even early in a disease process. The whole process may well take twenty years, the first half of which may be without overt symptoms.