Amyloid-

Mouse Serum amyloid A Alphai-acid glycoprotein Haptoglobin Alpha2-macroglobulin 

Rat Alphaj-macroglobulin Thiostatin Alphaj-acid glycoprotein Haptoglobin Fibrinogen Serum amyloid A 

Some references to the application and methods for some of these major acute phase proteins are provided in the list of references at the end of the chapter. 

This protein has a molecular mass of 41-43 kDa and in rats has an amino acid sequence that is 60% of the human protein. Antiserum to human alpha,-AGP cannot be used for rats and mice because there are at least two forms of the protein. Alpha,-AGP is synthesized primarily in the liver and the half-life is approximately 24 h. This protein transports hormones and cationic xenobiotics and may also act in nonspecific immunosuppression. 

Often called serum amyloid A (SAA), this protein has a low molecular mass of about 12 kDa, and there are at least three isoforms in mice and four in hamsters. These proteins are primarily produced in the liver, but they are also produced in several extrahepatic tissues such as the spleen and testes. These proteins are involved with regulating lipid metabolism and accelerate the removal of high-density lipoproteins from the circulation. The concentrations of amyloid A increase in mice where it is the primary acute phase protein, dogs and to a lesser degree in rats, despite some evidence has suggesting that SAA is not an acute phase protein in rats. Amyloid A should not be confused with amyloid P, which has much larger molecular masses of 230-300 kDa and a much more complex structure of 10 subunits. 

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Shiv]i A P, Brown F, Davies M C, Jennings K H, Roberts C J, Tendler S J B, Wilkinson M J and Williams P M 1995 Scanning tunnelling microscopy studies of p-amyloid fibril structure and assembly FEBS Lett. 371 25-8... 

Lansbury P T 1999 Evolution of amyloids What normal protein folding oan tell us about fibrillogenesis and disease Proc. Nati Acad. Sci. (USA) 96 3342-4... 

General trends in radiopharmaceutical research emphasize the use of small peptides. These molecules, of which the agents mentioned for thrombosis localization are an example, exhibit rapid and specific binding, and rapid blood clearance, two important parameters for a successflil radiopharmaceutical. Peptides are readily labeled with Tc and lend themselves to formulation as lyophilized kits that can be rapidly and rehably reconstituted. Possible targets for these molecules are quite varied, ranging from atherosclerotic plaque to P-amyloid (for Alzheimer s disease), to a variety of somatic receptors the populations of which are increased or decreased in disease. 

Fibrous proteins can serve as structural materials for the same reason that other polymers do they are long-chain molecules. By cross-linking, interleaving and intertwining the proper combination of individual long-chain molecules, bulk properties are obtained that can serve many different functions. Fibrous proteins are usually divided in three different groups dependent on the secondary structure of the individual molecules coiled-coil a helices present in keratin and myosin, the triple helix in collagen, and P sheets in amyloid fibers and silks. 

Amyloid fibrils are suggested to be built up from continuous P sheet helices... 

Figure 14.7 Ribbon diagram of one subunit of the globular form of transthyretin. The p strands are labeled A to H from the amino end. Strands C and D are thought to be unfolded to produce the conformation that forms amyloid fibrils. (Adapted from C.C.F. Blake et al., /. Mol. Biol. 121 339-356, 1978.)...

Progress in deducing more structural details of these fibers has instead been achieved using NMR, electron microscopy and electron diffraction. These studies reveal that the fibers contain small microcrystals of ordered regions of the polypeptide chains interspersed in a matrix of less ordered or disordered regions of the chains (Eigure 14.9). The microcrystals comprise about 30% of the protein in the fibers, are arranged in p sheets, are 70 to 100 nanometers in size, and contain trace amounts of calcium ions. It is not yet established if the p sheets are planar or twisted as proposed for the amyloid fibril discussed in the previous section. 

Fibrous proteins are long-chain polymers that are used as structural materials. Most contain specific repetitive amino acid sequences and fall into one of three groups coiled-coil a helices as in keratin and myosin triple helices as in collagen and p sheets as in silk and amyloid fibrils. 

Blake, C., Serpell, L. Synchrotron x-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous P sheet helix. Structure 4 989-998, 1996. 

These results indicate that is it possible to change the fold of a protein by changing a restricted set of residues. They also confirm the validity of the rules for stability of helical folds that have been obtained by analysis of experimentally determined protein structures. One obvious impliction of this work is that it might be possible, by just changing a few residues in Janus, to design a mutant that flip-flops between a helical and p sheet structures. Such a polypeptide would be a very interesting model system for prions and other amyloid proteins. 

Speck-, fatty, lardaceous. amyloid, speck-ahnlich, -artlg, a. fatty, lardaceous. Speck-glanz, m. greasy luster, -haut, /. (Physiol.) buffy coat. 

Acute phase reactants (e.g., C-reactive protein) are proteins that increase during inflammation and are deposited in damaged tissues. They were first discovered in the serum, but are now known to be involved in inflammatory processes in the brain (e.g., found in the brain of Alzheimer patients and associated with amyloid plaques). 

A number of adipokines are linked to inflammation and immunity (Fig. 1). This includes both leptin and adiponectin, and also a number of other key inflammatory proteins, particularly cytokines and chemokines [1]. The cytokines and chemokines encompass interleukin-1(3 (EL-1 (3), IL-6, DL-10, TNFa, monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor (MIF). Other major inflammation-related adipokines include nerve growth factor (NGF), and acute phase proteins such as serum amyloid A and haptoglobin. In addition, adipocytes secrete plasminogen activator inhibitor-1 (PAI-1), which is an important thrombotic factor as well as an acute phase protein. 

According to the amyloid hypothesis, the A 3 peptide plays a critical role in the pathogenesis of Alzheimer s disease [1]. Major forms of A 3 produced encompass 38, 40 or 42 residues. A 342 is more prone to aggregation than A 340 and in animal models an increased A[342/ A (340 ratio results in amyloid plaque pathology even when total A 3 levels are reduced [4]. The generation of A 3 is a normal process and A 3 is present in the brains and body fluids of humans throughout life. Neuronal... 

APP is a type-I transmembrane protein that is part of an evolutionarily conserved protein family, including the amyloid precursor-like proteins 1 (APLP1) and 2 (APLP2). APP and APLPs are functionally redundant and form homo- and hetero-oligomers. The absence of the A 3 sequence in the APLPs underlines the importance of APP that can only give rise to the A 3 species. Decreasing the formation of soluble A 3... 

Alzheimer s Disease. Figure 1 A(3 monomers can self-associate to form dimers, trimers and higher oligomers. Globular structures of synthetic A(342 are known as A(3-derived diffusible ligands (ADDLs) (3-12-mers of A(3). These structures are similar to the smallest protofibrils and represent the earliest macromolecular assembly of synthetic A(3. The characteristic amyloid fiber exhibits a high beta-sheet content and is derived in vitro by a nucleation-dependent self-association and an associated conformational transition from random to beta-sheet conformation of the A(3 molecule. Intermediate protofibrils in turn self-associate to form mature fibers. 

Dtugs in clinical development that directly target the A(3 pathway are at an early stage. Inhibitors of (3- and y-secretases that can lower the A 3 production have entered clinical phase trials with (3-secretase inhibitors being years behind the development of y-secretase inhibitors. Functional y-secretase inhibitors have been shown to reduce the rate of A 3 formation in vitro and in vivo. The reduction of A 3 monomer levels could prevent oligomer formation and subsequent syn-aptotoxicity. Numerous anti-amyloid approaches to... 

Masters CL Beyreuther K (2006). Alzheimer s centennial legacy prospects for rational therapeutic intervention targeting the AB amyloid pathway. Brain 129 2823-2839... 

Munter LM, Voigt P, Harmeier A et al (2007). GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of AB42. EMBO 126 1702-1712... 

This is an extracellular deposition of an insoluble protein, which has adopted a (3-sheet structure due to an unknown event that induced misfolding of unstable proteins. The name amyloid has been given according to the amyloid staining properties, which are similar to carbohydrate deposits, e.g., amyloid can be identified with Congo red and seen under polarized light (birefringence test). 

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