Amyloid pathway

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

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... 

Another pathway of influence in AD is the facilitation of amyloid- 3 (A 3) aggregation through an interaction with the PAS of AChE but not of BChE. Inversely, the usual BChE (and more specifically its C-terminus) was shown recently as to attenuate in vitro the formation of amyloid fibrils [4]. 

Lashuel HA, Lai Z, Kelly JW. Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation implications for wild-type, V30M, and L55P amyloid fibril formation. Biochemistry 1998 37 17851-17864. 

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. 

Bitan, G., Kirkitadze, M.D., Lomakin, A., Vollers, S.S., Benedek, G.B., and Teplow, D.B. (2003) Amyloid B-protein (otP) assembly ap40 and ap42 oligomerize through distinct pathways. Proc. Natl. Acad. Sci. USA 100, 330-335. 

AMYLOID FIBRIL ASSEMBLY PATHWAYS AND CYTOTOXICITY MECHANISMS... 

Now that we have defined the starting point and the final products of the assembly process, the next step is to investigate the origin of amyloid fibril polymorphism through a detailed study of the assembly pathways... 

In the case of human amylin and Afi our understanding of the diversity in amyloid fibril architecture is the result of a recursive process, since the early morphological observations were followed by assessment of the assembly pathway which in turn yielded a better understanding of fibril polymorphism. However, this structural knowledge is secondary compared to the discovery of small oligomers, globular oligomers, and early protofibrils that appear to be extremely cytotoxic (Hartley etal., 1999 Lambert et al, 1998 Walsh et al, 1999). 

Goldsbury, C., Frey, P., Olivieri, V., Aebi, U., and Muller, S. A. (2005). Multiple assembly pathways underlie amyloid-beta fibril polymorphisms./. Mol. Biol. 352, 282-298. 

Huff, M. E., Balch, W. E., and Kelly, J. W. (2003). Pathological and functional amyloid formation orchestrated by the secretory pathway. Curr. Opin. Struct. Biol. 13, 674-682. Jansen, R., Dzwolak, W., and Winter, R. (2005). Amyloidogenic self-assembly of insulin aggregates probed by high resolution atomic force microscopy. Biophys. J. 88, 1344-1353. 

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