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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.
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 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.
This book reviews current research on the important processes involved in neurodegenerative diseases (e.g. Alzheimer's disease) and the peptides and proteins involved in the amyloidogenic processes. It covers the design and developments of anti-amyloid inhibitors, and gives readers a fundamental understanding of the underlying oligomerization and aggregation processes of these diseases from both computational and experimental points of view.
This thesis presents a method for reliably and robustly producing samples of amyloid-β (Aβ) by capturing them at various stages of aggregation, as well as the results of subsequent imaging with various atomic force microscopy (AFM) methods, all of which add value to the data gathered by collecting information on the peptide’s nanomechanical, elastic, thermal or spectroscopical properties. Amyloid-β (Aβ) undergoes a hierarchy of aggregation following a structural transition, making it an ideal subject of study using scanning probe microscopy (SPM), dynamic light scattering (DLS) and other physical techniques. By imaging samples of Aβ with Ultrasonic Force Microscopy, a detailed substructure to the morphology is revealed, which correlates well with the most advanced cryo-EM work. Early stage work in the area of thermal and spectroscopical AFM is also presented, and indicates the promise these techniques may hold for imaging sensitive and complex biological materials. This thesis demonstrates that physical techniques can be highly complementary when studying the aggregation of amyloid peptides, and allow the detection of subtle differences in their aggregation processes.
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.
Abstract: It has been proposed that the amyloid [beta]-protein (A[beta]-protein) plays a crucial role in the development of Alzheimer's Disease (AD). This dissertation presents the results of computational studies of the initial stages of A[beta]-protein association. The objective of this work was to determine the stability and role of the A[beta]-protein monomers and low-order oligomers as metastable intermediates on the pathway for formation of larger aggregates and fibrils. A protocol based on shape complementarity is used to generate an assortment of possible dimer structures of the A[beta] 10--35 -protein congener. The ensemble of dinner structures are evaluated using rapidly computed estimates of the desolvation and electrostatic interaction energies to identify a putative stable dimer structure. Using the umbrella sampling method and classical molecular dynamics, the potential of mean force (PMF) associated with the dimerization of the peptide in aqueous solution is computed. The profiles of the PMF corresponding to the formation of the two putative dimer structures are compared. Molecular dynamics trajectories originating from the two putative dimer structures are used to analyze their stability. Significant attempts are made to increase the time over which the association of the A[beta] 10--35 -protein can be simulated. In this respect, conformations generated by the A[beta] 10--35 -protein simulated using an explicit TIP3P solvent model are compared to conformations resulting from simulations employing one empirical and two continuum electrostatics solvent models. Inspired by recent experimental results, the dynamics of the D23-K28 "salt-bridge" contacts are examined and critically evaluated as a, possible "nucleation site" for the formation of [beta]-structure characteristic of amyloid fibrils. The behavior of the A[beta] 21--30 -protein fragment is studied using molecular dynamics simulations employing an explicit aqueous solvent model. Special attention is paid to the VGSN(2427) region of the protein where experimental solid-state nuclear magnetic resonance (NMR) measurements indicate that formation of a turn may play a crucial role in stabilizing the A[beta] 1--42 -protein in fibril structure. The influence of two mutations, E22Q and D23N, on the thermodynamics properties of the A[beta] 21--30 fragment is analyzed and related to the possible roles played by these two naturally occurring mutations in amyloidosis.