Peptide amyloid

The enzymes that are involved in the processing of APP into amyloid peptides are known as secretases. Beta-secretase is an enzyme that catalyzes the initial proteolytic event leading to the production of Abeta amyloid peptides. If APP is cleaved by beta-secretase it can then be further cleaved by gamma-secretase. Abeta peptides are either secreted or intracellularly released. They have varying lengths and represent intermediate degradation products of its precursor (i.e., (3-secretase cleaved APP). Especially the 42 amino acid peptide (A 342) aggregates to form insoluble amyloid plaques. 

Alzheimer s disease in which the pathogenicity of amyloid peptides depends on proteases, namely secretases, involved in amyloid precursor protein (APP) maturation. This chapter will describe how the proteolysis of chemokines might participate in the neuropathogenesis of HIV infection, thus contributing to the development of the central nervous system disorder termed HIV-associated dementia (HAD). 

Auld, DS, Kar, S and Quiron, R (1998) /i-amyloid peptides as direct cholinergic neuromodulations a missing link Trends Neurosci. 21 43-49. 

Bihel, F. Quelever, G. Lelouard, H. Petit, A. Alves de Costa, C. Pourqie, O. Checler, F. Thellend, A. Pierre, P Kraus, J.-L. Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new beta-amyloid peptide production inhibitors and their activities on various classes of protease. Bioorg. Med. Chem. 2003, 11, 3141-3152. 

Burdick D, Soreghan B, Kwon M, Kosmoski J, Rnauer M, Henschen A, Yates J, Cotman C, Glabe C. Assembly and aggregation properties of synthetic Alzheimer s A4/beta amyloid peptide analogs. J Biol Chem 1992 267 546-554. 

Shen CL, Scott GL, Merchant F, Murphy RM. Light scattering analysis of fibril growth from the amino-terminal fragment beta(l-28) of beta-amyloid peptide. Biophys J 1993 65 2383-2395. 

Tomski SJ, Murphy RM. Kinetics of aggregation of synthetic beta-amyloid peptide. Arch Biochem Biophys 1992 294 630-638. 

Kowalewski T, Holtzman DM. In situ atomic force microscopy study of Alzheimer s beta-amyloid peptide on different substrates new insights into mechanism of beta-sheet formation. Proc Natl Acad USA 1999 96 3688-3693. 

Maggio JE, Stimson ER, Ghilardi JR, Allen CJ, Dahl CE, Whitcomb DC, et al. Reversible in vitro growth of Alzheimer disease (Vamyloid plaques by deposition of labeled amyloid peptide. Proc Natl Acad Sci USA 1992 89 5462-5466. 

Lee JP, Stimson ER, Ghilardi JR, Mantyh PW, Lu Y-A, Felix AM, Llanos W, Behbin A, Cummings M, Criekinge MV, Timms W, Maggio JE. 1H NMR of A(i amyloid peptide congeners in water solution. Conformational changes correlate with plaque competence. Biochemistry 1995 34 5191-5200. 

Dudek SM, Johnson GV. Transglutaminase facilitates the formation of polymers of the beta-amyloid peptide. Brain Res 1994 651 129-133. 

Howlett DR, Perry AE, Godfrey F, Swatton JE, Jennings KH, Spitzfaden C, Wadsworth H, Wood SJ, Markwell RE. Inhibition of fibril formation in beta-amyloid peptide by a novel series of benzofurans. Biochem J 1999 ... 

Liu Y, Schubert D. Cytotoxic amyloid peptides inhibit cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MMT) reduction by enhancing MTT formazan exocytosis. J Neurochem 1997 69 2285-2293. 

Figure 10-5. Representative conformations of the (5 amyloid peptide (10-42) under different pH conditions. The conformations were obtained as centroids of the most populated clusters from the replica-exchange CPHMD folding simulations [43, 44]. The N-terminal residues 10-28 are shown in blue the C-terminal residues 29-42 are shown in red. In the most aggregation-prone state (pH 6), the side chains of the central hydrophobic cluster Leu-17, Val-18, Phe-19, Phe-20 and Ala-21 are shown as van der Waals spheres in pink, grey, cyan, purple and green, respectively...

Khandogin J, Brooks CL III (2007) Linking folding with aggregation in Alzheimer s beta amyloid peptides. Proc Natl Acad Sci USA 104 16880-16885. 

Wood SJ, Maleeff B, Hart T, Wetzel R (1996) Physical, morphological and functional differences between pH 5.8 and 7.4 aggregates of the Alzheimer s amyloid peptide A. J Mol Biol 256(5) 870-877... 

Abundant neuritic plaques and neurofibrillary lesions define Alzheimer s disease. Plaques are extracellular deposits made of the fibrillar P-amyloid peptide. The paired helical filament (PHF) makes up the bulk of the intraneuronal neurofibrillary pathology of Alzheimer s disease, with the straight filament (SF) being a minority species. 

Serum antibodies serve as a sink to draw the amyloid peptides from the brain into the circulation, thus changing the equilibrium of AP in different compartments and promoting removal of AP from the brain [82, 84, 85, 88]. 

Jankowsky, J. L., Fadale, D. J., Anderson, J. et al. Mutant presenilins specifically elevate the levels of the 42 residue P-amyloid peptide in vivo evidence for augmentation of a 42-specific y-secretase. Hum. Mol. Genet. 13 159-170, 2004. 

Figure 17.5. The precursor molecule APP and the three different proteases a, (i, y secretase that are involved in the processing of APPto fS-amyloid peptide. The aberrant processing of the amyloid precursor protein (APP) leads to accumulation of beta-amyloid fragments, first as protofibrils and then as fibers that aggregate in the senile plaque structures. (See color insert.)...

Balbach, J. J., Ishii, Y., Antzutkin, O. N., Leapman, R. D., Rizzo, N. W., Dyda, F., Reed,J., and Tycko, R. (2000). Amyloid fibril formation by A beta 16-22, a seven-residue fragment of the Alzheimer s beta-amyloid peptide, and structural characterization by solid state NMR. Biochemistry 39, 13748-13759. 

Lomakin et al., 1996). Surface plasmon resonance studies of the A/ (l—40) /1-amyloid peptide (Cannon et al., 2004) provide even more details of the multiple kinetic steps, and suggest that fibril formation proceeds by reversible addition of a monomer to the tip of the formed fibril, followed by a postbinding, transitional event. 

Hope, J., Shearman, M. S., Baxter, H. C., Chong, A., Kelly, S. M., and Price, N. C. (1996). Cytotoxicity of prion protein peptide (PrP106-126) differs in mechanism from the cytotoxic activity of the Alzheimer s disease amyloid peptide, A [S 25-35. Neurodegeneration 5, 1-11. 

Mason, R. P., Estermyer, J. D., Kelly, J. F., and Mason, P. E. (1996). Alzheimer s disease amyloid // peptide 25-35 is localized in the membrane hydrocarbon core X-ray diffraction analysis. Biochem. Biophys. Res. Commun. 222, 78-82. 

Unfortunately, the description of amyloid fibrils given above is simplistic since in vitro self-assembly of amyloid peptides and proteins yields polymorphic structures, as has been commonly observed in the past for other protein assemblies such as actin filaments (Millonig et al, 1988) and intermediate filaments (Herrmann and Aebi, 1999). On the one hand, assembly polymorphism complicates the characterization of fibril structure. On the other hand, it offers some insight into fibril formation. For this reason a more rational understanding of amyloid fibril formation at the molecular level is a key issue in the field of amyloidosis. 

Concerning the nature and structure of such amyloid peptide or protein channels, oligomers with annular morphologies have in fact been observed by EM for a-synuclein (Lashuel et al., 2002) and equine lysozyme (Malisauskas et al., 2003) even in the absence of any lipids or membranes. Channel-like structures have also been reconstituted in liposomes and observed by SFM for A/ i 4o, A/ j 42, human amylin, a-synuclein, ABri, ADan, and serum amyloid A (Fig. 5A Lin et al., 2001 Quist et al., 2005). Doughnut-shaped structures with a diameter of 10-12 nm and a central hole size of 1-2 nm (Fig. 5B) were imaged on top of lipid membranes (Quist et al., 2005). However, the radius of curvature of the SFM tips meant that it is not possible to say whether the pores were really traversing the lipid bilayer. 

Hertel, C., Terzi, E., Hauser, N., Jakob-Rotne, R., Seelig, J., and Kemp, J. A. (1997). Inhibition of the electrostatic interaction between beta-amyloid peptide and membranes prevents beta-amyloid-induced toxicity. Proc. Natl. Acad. Sd. USA 94, 9412-9416. 

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