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In Alzheimer's Disease (AD), the Amyloid Precursor Protein (APP) is endoproteolytically cleaved by beta-secretase to liberate beta-stub and subsequently processed by beta-secretase to produce Amyloid-beta (AP). Considering these endoproteolytic products have been implicated in AD pathogenesis, we have modified APP such that the cytoplasmic domain is absent and unable to support full-length beta-stub synthesis, yet able to produce full-length Abeta. By engineering mice with this transgene, we can assess whether Abeta or beta-stub cause cognitive deficits as compared to TgCRND8 mice that support synthesis of full length APP, beta-stub and Abeta. Moreover, transgenes with an altered APP copper binding domain (CuBD) have been made to prevent the post-natal lethality seen in TgCRND8 mice, while still exhibiting AD pathology. Through genetic, biochemical, and behavioural analyses of our transgenic mouse models, we will be able to define the contributions of the cytoplasmic tail and the CuBD of APP in AD pathogenesis.
In the search for an effective treatment for Alzheimer's disease, APP is a unique model protein that illustrates the wide array of basic and sophisticated characterization techniques available. Exploring a variety of biological techniques to clarify the structure and function of this transmembrane protein, this text presents each method with detail
This book summarizes the last ten years' research on Alzheimer's disease. Genetic mutations in the gene which codes for amyloid precursor protein (APP) have now been shown to cause Alzheimer's disease in some families. Other genetic loci are now being discovered which relate to Alzheimer's disease in some families. Understanding the normal structure and function of the APP gene product will eventually provide avenues for developing specific therapeutic strategies targeted at the amyloid deposition in the Alzheimer's disease brain. Drugs which can inhibit or dissolve the amyloid, affect the synthesis and proteolysis of APP, or which regulate the activity of the APP gene all hold the promise of eventually yielding an effective treatment for Alzheimer's disease.
The amyloid precursor protein APP plays a key role in the pathogenesis of Alzheimer’s disease (AD), as proteolytical cleavage of APP gives rise to the Aβ peptide which is deposited in the brains of Alzheimer patients. Despite this, our knowledge of the normal cell biological and physiological functions of APP and the closely related APLPs is limited. This may have hampered our understanding of AD, since evidence has accumulated that not only the production of the Aβ peptide but also the loss of APP-mediated functions may contribute to AD pathogenesis. Thus, it appears timely and highly relevant to elucidate the functions of the APP gene family from the molecular level to their role in the intact organism, i.e. in the context of nervous system development, synapse formation and adult synapse function, as well as neural homeostasis and aging. Why is our understanding of the APP functions so limited? APP and the APLPs are multifunctional proteins that undergo complex proteolytical processing. They give rise to an almost bewildering array of different fragments that may each subserve specific functions. While Aβ is aggregation prone and neurotoxic, the large secreted ectodomain APPsα - produced in the non-amyloidogenic α-secretase pathway - has been shown to be neurotrophic, neuroprotective and relevant for synaptic plasticity, learning and memory. Recently, novel APP cleavage pathways and enzymes have been discovered that have gained much attention not only with respect to AD but also regarding their role in normal brain physiology. In addition to the various cleavage products, there is also solid evidence that APP family proteins mediate important functions as transmembrane cell surface molecules, most notably in synaptic adhesion and cell surface signaling. Elucidating in more detail the molecular mechanisms underlying these divers functions thus calls for an interdisciplinary approach ranging from the structural level to the analysis in model organisms. Thus, in this research topic of Frontiers we compile reviews and original studies, covering our current knowledge of the physiological functions of this intriguing and medically important protein family.
I entered the gene therapy field in the mid-1990s, being fascinated by the immense potential of genes as drugs for the treatment of human disease. Since then, I have experienced the ups and downs of this discipline, and tried to contribute with my work and that of my laboratory to the development of innovative approaches to the treatment of cardiovascular disorders. During these years, I have had several opp- tunities to speak on gene therapy at lectures and academic lessons, and have often noticed that the field is very attractive to scientists of all disciplines. However, as yet no comprehensive book on the subject has been published. Indeed, most books in the field are either a collection of gene transfer laboratory protocols or deal with the subject in a rather superficial manner. Hence the idea to write a gene therapy textbook that is broad and comprehensive, but at the same time provides sufficient molecular and clinical detail to be of interest to students, professors, and specialists in the various disciplines that contribute to gene therapy. I have tried to keep the language plain and, whenever possible, non-technical. Since the book is intended to be a textbook in the field of gene therapy in both the basic science and clinical areas, whenever technical descriptions are required, they are provided.
"This volume presents methods for the analysis of genomic variability in vertebrate neurons and broadens our knowledge in the ways we understand the brain and its neurons. The chapters in this book are divided into 5 parts, and cover the following topics: principles and approaches for discovery of somatic mosaicism in the brain, aneuploidy and ploidy variation, DNA copy number variation, LINE-1 retrotransposition, and genetic and genomic mosaicism in aging and disease. In Neuromethods series style, chapters include the kind of detail and key advice from the specialists needed to get successful results in your laboratory. Cutting-edge and authoritative, Genomic Mosaicism in Neurons and Other Cell Types is a valuable resource for learning about the latest techniques for the analysis of genome and genetic mosaicism in vertebrate neurons"--Publisher's description.
A considerable amount of information has been gathered in the field of immunoneurology over recent years. This knowledge about modifications in the pathways of neuroimmune diseases has enabled the development of new therapies. In this volume leading experts present the state of the art in the field, covering all aspects from basic science to the development of better therapies.