Alzheimer's disease (AD) is the most common form of dementia in adults and represents the fourth cause of death in the United States. At the present time there is no treatment for this disease. AD is neuropathologically characterized by the presence of amyloid deposition in the form of extracellular neuritic plaques and amyloid angiopathy. It has been proposed that amyloid fibril formation is one of the first events in the etiology of AD. The main component of amyloid is a 39-44 residues hydrophobic peptide called amyloid beta- peptide (Abeta), which is also found in a soluble form, normally circulating in human cerebrospinal fluid and plasma. Amyloid formation appears to be driven by hydrophobic interactions and dependent on conformational changes in the Abeta molecule. It seems that the basic unit for fibrillogenesis is the Abeta conformer adopting an antiparallel beta-sheet composed of strands involving the regions 10- 24 and 29-40/42 of Abeta. Amyloid formation would proceed by hydrophobic interactions between the beta-strands of several monomers to form an oligomeric beta-sheet structure precursor of the fibrillar beta-cross conformation. In the present application we propose to use the knowledge of the structural determinants of amyloid formation in a rational design of inhibitors of the fibrillogenesis process. Our hypothesis is that short peptides homologous to Abeta but containing amino acids which block the formation of the beta-sheet structure, will inhibit fibril formation. The specific aims of this proposal include the design of a set of potentially inhibitory peptides of amyloid formation according the hypothesis and to test whether these peptides are able to inhibit fibrillogenesis in vitro and in vivo, using an animal model of amyloidosis related to amyloid-A. Furthermore, the best inhibitor will be improved to make an analog having a higher avidity for Abeta, a higher resistance to proteolytic degradation and a lower immunogenicity. Preliminary results indicate that an 11 residues peptide designed according the hypothesis, was able to binds to Abeta, inhibits the Abeta fibril formation by 80% and redissolves almost completely preformed fibrils in vitro, when used in a molar excess of 10 times. Furthermore, in a pilot study using the amyloid-A animal model of amyloidosis, the peptide arrested amyloid deposition in vivo. Considering the apparent causal role of amyloid in the pathogenesis of AD, the findings generated by this project may create new avenues in the design of drugs to be used in the treatment of AD.
NIH ExPorter
NIH ExPorter