Regulation Of Amyloid Beta Protein Levels By Proteolytic Degradation And Its Implications For Alzheimers Disease

Accumulation and deposition of the amyloid beta-protein (A[beta]) is an invariant feature of Alzheimer's disease (AD). Biochemical, cell biological, animal modeling, genetic, and emerging clinical data all suggest that A[beta] is an upstream initiator of the disease process and its neuropathology. Decreasing brain A[beta] is an emerging therapeutic approach for AD, and currently efforts are being made to block A[beta] production or enhance its clearance through vaccination. A less well understood mechanism of A[beta] clearance is enzymatic degradation by proteases within the brain. The purpose of this thesis is to describe pathways of A[beta] catabolism that may shed light on disease pathogenesis. Further, such insight may prove useful for assessing disease risk as well as offering preventative and therapeutic measures against the disease. I first present evidence that an enzyme genetically associated with AD, the angiotensin-converting enzyme (ACE), is an A[beta]-degrading protease. I determine that ACE is expressed within the brain, and that cellular overexpression of ACE promotes the degradation of A[beta].

Strong evidence continues to accumulate indicating that amyloid-beta (Aß) is a central part of Alzheimer’s disease (AD) pathogenesis in spite of the negative evidence coming from failed clinical trials. Therefore, mechanisms of clearance of Aß are of great interest in understanding AD pathogenesis and the development of effective treatments. This topic focuses on the issues related to Aß clearance in AD. The topics covered include proteases that degrade Aß and their localization, regulation, and functions. This topic also covers issues related to clearance through uptake by glia and through low-density lipoprotein (LDL) receptor mediated mechanisms. Signal transduction related to AD pathology and clearance is also addressed. Finally, immunotherapy and other novel therapeutic approaches are discussed.

The brain is the most complex organ in our body. Indeed, it is perhaps the most complex structure we have ever encountered in nature. Both structurally and functionally, there are many peculiarities that differentiate the brain from all other organs. The brain is our connection to the world around us and by governing nervous system and higher function, any disturbance induces severe neurological and psychiatric disorders that can have a devastating effect on quality of life. Our understanding of the physiology and biochemistry of the brain has improved dramatically in the last two decades. In particular, the critical role of cations, including magnesium, has become evident, even if incompletely understood at a mechanistic level. The exact role and regulation of magnesium, in particular, remains elusive, largely because intracellular levels are so difficult to routinely quantify. Nonetheless, the importance of magnesium to normal central nervous system activity is self-evident given the complicated homeostatic mechanisms that maintain the concentration of this cation within strict limits essential for normal physiology and metabolism. There is also considerable accumulating evidence to suggest alterations to some brain functions in both normal and pathological conditions may be linked to alterations in local magnesium concentration. This book, containing chapters written by some of the foremost experts in the field of magnesium research, brings together the latest in experimental and clinical magnesium research as it relates to the central nervous system. It offers a complete and updated view of magnesiums involvement in central nervous system function and in so doing, brings together two main pillars of contemporary neuroscience research, namely providing an explanation for the molecular mechanisms involved in brain function, and emphasizing the connections between the molecular changes and behavior. It is the untiring efforts of those magnesium researchers who have dedicated their lives to unraveling the mysteries of magnesiums role in biological systems that has inspired the collation of this volume of work.

To understand Alzheimer's disease (AD) is one of the major thrusts of present-day clinical research, strongly supported by more fimdamental 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 standardization between the Chapters, but some minor yet acceptable personal / author variation is still present, i. e. P-amyloid/amyloid-P; Ap42/Apl-42/APi. 42! The book commences with a broad survey of the contribution that the range of available microscopical techniques has made to the study of Alzheimer'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.

There is now considerable genetic evidence that the type 4 allele of the apolipoprotein E gene is a major susceptibility factor associated with late-onset Alzheimer's disease, the common form of the disease defined as starting after sixty years of age. The role of apolipoprotein E in normal brain metabolism and in the pathogenesis of Alzheimer's disease are new and exciting avenues of research. This book, written by the most outstanding scientists in this new filed, is the first presentation of results concerning the implications of apolipoprotein E on the genetics, cell biology, neuropathology, biochemistry, and therapeutic management of Alzheimer's disease.

These 22 papers cover protein trafficking, lysosomal proteolysis, calpains, serpins, processing of cytoskeletal proteins, and complex proteolytic cascades of the circulatory system.

This book highlights the pathophysiological complexities of the mechanisms and factors that are likely to be involved in a range of neuroinflammatory and neurodegenerative diseases including Alzheimer's disease, other Dementia, Parkinson Diseases and Multiple Sclerosis. The spectrum of diverse factors involved in neurodegeneration, such as protein aggregation, oxidative stress, caspases and secretase, regulators, cholesterol, zinc, microglia, astrocytes, oligodendrocytes, etc, have been discussed in the context of disease progression. In addition, novel approaches to therapeutic interventions have also been presented. It is hoped that students, scientists and clinicians shall find this very informative book immensely useful and thought-provoking.

Alzheimer’s disease is a progressive neurodegenerative disease and the most common type of dementia. One of AD hallmarks is the deposition of amyloid [beta] (A-[beta]), a peptide generated from proteolytic processing of its precursor, amyloid precursor protein (APP). Canonical APP proteolysis occurs via [alpha]-/ [beta]- and [gamma]-secretases. APP is also actively degraded by protein degradation systems. By pharmacologically inhibiting protein degradation with ALLN, we observed an accumulation of heretofore undocumented APP fragments (CTFs). The two major novel CTFs migrated around 15 and 25 kD. The process was independent of cytotoxicity or protein synthesis. The build-up of the novel CTFs are not mediated by proteasome or calpain inhibition, but by cathepsin inhibition. Moreover, these novel CTFs are not generated by increased amount of BACE. Here, we name the CTF of 25 kD as [eta]-CTF. Our data suggests that under physiological conditions, a subset of APP undergoes alternative processing and the intermediate products, the 15 kD- and the 25 kD-CTFs ([eta]-CTF) get rapidly degraded/ processed via the protein degradation machinery, specifically, cathepsin.

La maladie d'Alzheimer est un syndrome neurodégénératif caractérisé par la présence de plaques séniles et de dégénérescences neurofibrillaires. Le constituant majeur des plaques séniles est le peptide [beta]-amyloïde (A[beta]) qui est issu de la maturation protéolytique de la protéine précurseur du peptide [beta]-amyloïde ( [beta]APP). Deux activités enzymatiques, les [beta]- et [gamma]- sécrétases libèrent respectivement les extrémités N- et C-terminales du peptide A[beta]. La [beta]APP peut subir une maturation protéolytique alternative dans la séquence du peptide A[beta] par une [alpha]-sécrétase, prévenant ainsi la production du peptide amyloïde. De plus, le clivage [alpha]-sécrétase génère un fragment soluble (APP[alpha]) qui est neurotrophique et citoprotecteur. La maturation de la [beta]APP est sous le contôle de voies de phosphorylation, comme la voie régulée par la protéine kinase C (PKC). (...).

A proven collection of readily reproducible techniques for studying amyloid proteins and their involvement in the etiology, pathogenesis, diagnosis, and therapy of amyloid diseases. The contributors provide methods for the preparation of amyloid and its precursors (oligomers and protofibrils), in vitro assays and analytical techniques for their study, and cell culture models and assays for the production of amyloid proteins. Additional chapters present readily reproducible techniques for amyloid extraction from tissue, its detection in vitro and in vivo, as well as nontransgenic methods for developing amyloid mouse models. The protocols follow the successful Methods in Molecular BiologyTM series format, each offering step-by-step laboratory instructions, an introduction outlining the principle behind the technique, lists of the necessary equipment and reagents, and tips on troubleshooting and avoiding known pitfalls.