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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.
Amyloid precursor protein (APP) is a type one transmembrane protein and has two mammalian homologues, amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2). APP is the parent molecule to amyloid-[beta] (A[beta]), the amyloidogenic species found in the plaques of people with Alzheimer's disease (AD). Several lines of evidence suggest A[beta] to lie at the center of AD pathology, with converging evidence to indicate that synapses are the site of the initial damage. Recent studies have shown that APP may be necessary for the toxicity induced by A[beta], in part by cleavage of a caspase site on the intracellular domain of the APP protein and the subsequent release of the toxic molecule, C31. This caspase cleavage is shown to induce APP-mediated A[beta] toxicity in cell culture models, however assays were based on contribution to cell death. Thus, the physiologic relevance of the cleavage event has never been tested and in particular, whether this pathway contributes to synaptic damage is unclear. Here, we seek to test the role of caspase cleavage of APP in A[beta]-induced synaptic damage and to test the specificity of this event by testing whether caspase cleavage of APLP2, the protein most homologous to APP, also contributes to these A[beta]-driven synaptic changes. Additionally, because APP dimerization was shown to be necessary for the A & beta;-induced caspase cleavage of APP and subsequent release of C31, we wanted to test the effects of dimerization on APP proteolysis and A[beta] production.
Alzheimer's Disease (AD) is a neuropathological disorder characterized by the progressive deposition of insoluble amyloid plaques and vascular deposits consisting primarily of 4.5 kDa amyloid beta peptides (Abeta). There is increasing evidence that the deposition of Abeta fibrils in the brain, an invariable feature of AD, and/or prefibrillar aggregates likely cause neurodegeneration in AD. While Abeta fibrils were a previous research focus, recent experiments implicate prefibrillar aggregates as the toxic species. The identification and characterization of prefibrillar aggregates is of great importance to understanding AD and the development of therapeutic strategies. Biophysical and spectroscopic techniques were used to examine the effects of electrostatic interactions on Abeta oligomerization. Experimental work demonstrated that, while salt bridges likely provide stability to preformed Abeta aggregates, these interactions are not essential for the early stages of aggregation. Abeta oligomerization is driven by the formation of pH-independent interactions and is impeded by electrostatic repulsion at pH values away from the isoelectric point. Diffuse plaques, containing only the 42-residue form of Abeta, are unstructured and non-toxic; they appear before toxic senile plaques containing both 40 and 42-residue forms. Through incubation, Abeta40 and Abeta42 were shown to co-incorporate into unstructured aggregates early during fibrillogenesis later leading to tightly packed aggregates with secondary structure. Previously, the stage at which the Abeta variants co-incorporated during the fibrillogenic process was unknown. After observing that the amyloid precursor protein transmembrane (APP-TM) domain contains two known dimerization motifs (GXXXG/A), oligomerization of the APP-TM domain was examined. A model system was developed to investigate the effects of familial AD mutations on the dimerization propensity of APP-TM domains. This work culminated in the first experimentally supported mechanism to explain how genetic mutations within the APP gene lead to the observed phenotype and predisposition to AD. Further experimentation led to the discovery of non-denaturing detergents that stabilize suspected on-pathway spherical Abeta aggregates. These detergent-stabilized Abeta oligomers share many of the structural features and biological activities of both membrane bound Abeta and spherical oligomers of Abeta formed in solution. Thus, these stabilizing detergents may prove useful in high-resolution structural analysis of spherical oligomers.
We also found that dimerization of APP is sufficient to promote the amyloidogenic pathway, by increasing levels of the Î2-secretase BACE1, resulting in increased AÎ2 production. Finally, we found that dimerization of APP triggered caspase-dependent cleavage of APP and the formation of a second neurotoxic fragment, termed C31, which also mimics the effects of AÎ2 in hippocampal neurons. Taken together, our data provides support for the occurrence of a positive pathogenic feedback loop involving AÎ2, APP and C31 in neurons.
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
The nervous system is highly fragile, especially during aging, illness and trauma. This book addresses a small sampling of major constituents of neural function at the cellular and molecular level that play crucial roles in development and aging.
About the Series... Metal Ions in Life Sciences links coordination chemistry and biochemistry in their widest sense and thus increases our understanding of the relationship between the chemistry of metals and life processes. The series reflects the interdisciplinary nature of Biological Inorganic Chemistry and coordinates the efforts of scientists in fields like biochemistry, inorganic chemistry, coordination chemistry, molecular and structural biology, enzymology, environmental chemistry, physiology, toxicology, biophysics, pharmacy, and medicine. Consequently, the volumes are an essential source for researchers active in these and related fields as well as teachers preparing courses, e.g., in Bioinorganic Chemistry. About this Book... Volume 1, devoted solely to the vital research area concerning the role of metal ions in neurodegenerative diseases, offers in 15 stimulating chapters an authoritative and timely view of this fascinating subject. Written by 41 internationally recognized experts, Neurodegenerative Diseases and Metal Ions highlights, supported by 130 illustrations, the recent progress made in understanding the role metal ions play in diseases like transmissible spongiform encephalopathies (Creutzfeldt-Jakob and related diseases), Alzheimer's, Parkinson's, Huntington's, Wilson's and Menkes' diseases, as well as in familial amyotrophic lateral sclerosis and others. The interplay between metal ions, catecholamines and the formation of reactive oxygen species resulting in oxidative stress is considered, as is the metalloneurochemistry of zinc and the neurotoxicity of aluminum, cadmium, lead, and mercury. The need for novel drugs which manipulate metal-centered neuropathology is emphasized.
Neuroscience Perspectives provides multidisciplinary reviews of topics in one of the most diverse and rapidly advancing fields in the life sciences.Whether you are a new recruit to neuroscience, or an established expert, look to this series for 'one-stop' sources of the historical, physiological, pharmacological, biochemical, molecular biological and therapeutic aspects of chosen research areas.The last decade has seen tremendous advances in our understanding of the pathobiology of Alzheimer's disease. These will lead to the first generation of drugs aimed at prevention rather than cure. This book covers some of the most important and exciting of these advances, with chapters written by many of the leading researchers in the field.With genetic studies as a backbone to this volume many chapters are devoted to the function and regulation of amyloid b-protein precursor (APP) and apolipoprotein E (ApoE). Other chapters describe cell biological approaches helping to piece together the link between the genetic alterations and the phenotype we call Alzheimer's disease.Although APP and its proteolytic cleavage product, amyloid b-protein, do not answer all the questions, detailed research into this system has undoubtedly increased our knowledge of the pathobiology of AD and has lead to the identification of other risk factors. Understanding the role of ApoE in the pathology of Alzheimer's disease promises to open a whole new field in AD research. * * Reviews the current knowledge of the pathogenesis of Alzheimer's Disease from a clinical perspective to a genetic and cell biological perspective* A comprehensive description of the role of amyloid B-protein precursor in Alzheimer's disease.* Up-to-date research data* Clear illustrations complement the text