Synthetic Peptide Homologous to β Protein from Alzheimer Disease Forms Amyloid-Like Fibrils in vitro

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 84; no. 19; pp. 6953 - 6957
• Main Authors: Kirschner, Daniel A., Inouye, Hideyo, Duffy, Lawrence K., Sinclair, Alison, Lind, Marcia, Selkoe, Dennis J.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.10.1987; National Acad Sciences
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimers disease; Amino acids; Aminoacids, peptides. Hormones. Neuropeptides; Amyloid plaque; Amyloids; Analytical, structural and metabolic biochemistry; Antibodies; Biological and medical sciences; Electron microscopy; Fundamental and applied biological sciences. Psychology; Humans; Magnification; Microscopy, Electron; Peptides - chemical synthesis; Peptides - metabolism; Protein Conformation; Proteins; Solar fibrils; Structure-Activity Relationship; X ray diffraction; Human; Brain; Peptides; Alzheimer disease; Pathogenesis; Ageing; Homology; In vitro; Proteins; Synthetic product; Amyloid; Models; Fibril
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.84.19.6953

Progressive amyloid deposition in senile plaques and cortical blood vessels may play a central role in the pathogenesis of Alzheimer disease. We have used x-ray diffraction and electron microscopy to study the molecular organization and morphology of macromolecular assemblies formed by three synthetic peptides homologous to β protein of brain amyloid: β -(1-28), residues 1-28 of the β protein; [Ala16]β -(1-28), β -(1-28) with alanine substituted for lysine at position 16; and β -(18-28), residues 18-28 of the β protein. β -(1-28) readily formed fibrils in vitro that were similar in ultrastructure to the in vivo amyloid and aggregated into large bundles resembling those of senile plaque cores. X-ray patterns from partially dried, oriented pellets showed a cross-β -conformation. A series of small-angle, equatorial maxima were consistent with a tubular fibril having a mean diameter of 86 angstrom and a wall composed of pairs of cross-β -pleated sheets. The data may also be consistent with pairs of cross-β -sheets that are centered 71- angstrom apart. [Ala16]β -(1-28) formed β -pleated sheet assemblies that were dissimilar to in vivo fibrils. The width of the 10- angstrom spacing indicated stacks of about six sheets. Thus, substitution of the uncharged alanine for the positively charged lysine in the β -strand region enhances the packing of the sheets and dramatically alters the type of macromolecular aggregate formed. β -(18-28) formed assemblies that had even a greater number of stacked sheets, ≈ 24 per diffracting domain as indicated by the sharp intersheet reflection. Our findings on these homologous synthetic assemblies help to define the specific sequence that is required to form Alzheimer-type amyloid fibrils, thus providing an in vitro model of age-related cerebral amyloidogenesis.