Inhibition of beta-amyloid(40) fibrillogenesis and disassembly of beta-amyloid(40) fibrils by short beta-amyloid congeners containing N-methyl amino acids at alternate residues

A potential goal in the prevention or therapy of Alzheimer's disease is to decrease or eliminate neuritic plaques composed of fibrillar beta -amyloid (A beta). In this paper we describe N-methyl amino acid containing congener s of the hydrophobic "core domain" of A beta that inhibit the fibrillogenes is of full-length A beta. These peptides also disassemble preformed fibrils of full-length A beta. A key feature of the inhibitor peptides is that the y contain N-methyl amino acids in alternating positions of the sequence. Th e most potent of these inhibitors, termed A beta 16-22m, has the sequence N H2-K(Me-L)V(Me-F)F(Me-A)E-CONH2. In contrast, a peptide, NH2-KL(Me-V)(Me-F) (Me-F)(Me-A)-E-CONH2, with N-methyl amino acids in consecutive order, is n ot a fibrillogenesis inhibitor. Another peptide containing alternating N-me thyl amino acids but based on the sequence of a different fibril-forming pr otein, the human prion protein, is also not an inhibitor of A beta 40 fibri llogenesis. The nonmethylated version of the inhibitor peptide, NH2-KLVFFAE -CONH2 (A beta 16-22), is a weak fibrillogenesis inhibitor. Perhaps contrar y to expectations, the A beta 16-22m peptide is highly soluble in aqueous m edia, and concentrations in excess of 40 mg/mL can be obtained in buffers o f physiological pH and ionic strength, compared to only 2 mg/mL for A beta 16-22. Analytical ultracentrifugation demonstrates that A beta 16-22m is mo nomeric in buffer solution. Whereas A beta 16-22 is susceptible to cleavage by chymotrypsin, the methylated inhibitor peptide A beta 16-22m is complet ely resistant to this protease. Circular dichroic spectroscopy of A beta 16 -22m indicates that this peptide is a beta -strand, albeit with an unusual minimum at 226 nm. In summary, the inhibitor motif is that of alternating N -methyl and nonmethylated amino acids in a sequence critical for A beta 40 fibrillogenesis, These inhibitors appear to act by binding to growth sites of A beta nuclei and/or fibrils and preventing the propagation of the netwo rk of hydrogen bonds that is essential for the formation of an extended bet a -sheet fibril.