Amyloid intermediate

Nybo M, Svehag SE, Holm Nielsen E. An ultrastructural study of amyloid intermediates in A beta(l-42) fibrillogenesis. Scand J Immunol 1999 49 219-223. 

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. 

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. 

In the search for fibril formation inhibitors, the self-association to form amyloid fibrils of the A(3 peptides containing 40 and 42 amino acids can be treated as a coupled protein folding and polymerization process passing through multiple intermediate peptide species. The in vitro challenge is (1) to identify the various conformational forms and... 

Lai Z, Colon W, Kelly JW. The acid-mediated denaturation pathway of transthyretin yields a conformational intermediate that can self-assemble into amyloid. Biochemistry 1996 35 6470-6482. 

Walsh DM, Hartley DM, Kusomoto Y, Fezoui Y, Condron MM, Lomakin A, Benedek GB, Selkoe DJ, Teplow DB. Amyloid fi-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem 1999 274 25949-25952. 

Mullan M. Alzheimer s beta-amyloid vasoactivity identification of a novel beta-amyloid conformational intermediate. FEBS Lett 1998 436 445-448. 

It has been suggested recently that PPII helix may be the killer conformation in such diseases (Blanch et al., 2000). This was prompted by the observation, described in Section III,B, of a positive band at 1318 cm-1, not present in the ROA spectrum of the native state, that dominates the ROA spectrum of a destabilized intermediate of human lysozyme (produced by heating to 57°C at pH 2.0) that forms prior to amyloid fibril formation. Elimination of water molecules between extended polypeptide chains with fully hydrated 0=0 and N—H groups to form... 

IV. Depicting Intermediate Stages of Amyloid Fibril Assembly.. . 223... 

Zhu, L., Zhang, X. J., Wang, L. Y., Zhou, J. M., and Perrett, S. (2003). Relationship between stability of folding intermediates and amyloid formation for the yeast prion Ure2p A quantitative analysis of the effects of pH and buffer system./ Mol. Biol. 328, 235-254. 

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. 

In this chapter, we first describe amyloid fibril polymorphism as seen by EM. We then show how SFM was used to depict intermediate stages of amyloid fibril assembly. Finally, we discuss the putative mechanism that might explain the cytotoxicity induced by these assembly intermediates. 

Hartley, D. M., Walsh, D. M., Ye, C. P., Diehl, T., Vasquez, S., Vassilev, P. M., Teplow, D. B., and Selkoe, D. J. (1999). Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical... 

The extreme stability of amyloid and amyloid-like fibrils is difficult to understand in terms of the three classes of fibril models. For the Refolding models, it has been suggested that the amyloid conformation is a default conformation for a polypeptide chain (Dobson, 1999). However, these models do not give a clear indication of what types of interactions differ in the amyloid conformation versus the native conformation, and so it is unclear why the amyloid conformation should be more stable. Also, it seems that the elevated protein concentrations associated with fibril formation might disproportionately favor nonspecific aggregation of the destabilized intermediate over amyloid fibril formation. 

Olofsson, A., Ippel, H. J., Baranov, V., Horstedt, P., Wijmenga, S., and Lundgren, E. (2001). Capture of a dimeric intermediate during transthyretin amyloid formation. / Biol. Chem. 276, 39592-39599. 

To test the feasibility of enzyme-catalyzed enantiosective reactions in solid/gas reactors and to evaluate the efficiency of the resolution obtained in the gas phase compared to liquid systems, resolution of racemic 2-pentanol, catalyzed by CALB, through alcoholysis with methyl propanoate as acyl donor has been investigated in both liquid media and the gas phase [24]. As CALB has an enantiopreference for R enantiomers of secondary alcohols, this last reaction leads to S-2-Pentanol. This compound is a chiral intermediate in the synthesis of several potential anti-Alzheimer s drugs that inhibit 3-amyloid peptide release and/or its synthesis [25]. The degree of enantioselectivity was measured by using the enantiomeric ratio E, which is defined as the ratio of the specificity constants kcat/KM for the enantiomers (R/S in this case). E can be determined from the enantiomeric excess of... 

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