Synthetic peptide homologous to. beta. protein from Alzheimer's disease forms amyloid-like fibrils in vitro

Kirschner, D A; Inouye, H; Duffy, L K; Sinclair, A; Lind, M; Selkoe, D J

doi:10.1073/pnas.84.19.6953

Title: Synthetic peptide homologous to. beta. protein from Alzheimer's disease forms amyloid-like fibrils in vitro

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Abstract

Progressive amyloid deposition in senile plaques and cortical blood vessels may play a central role in the pathogenesis of Alzheimer's disease. The authors 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 ..beta.. protein of brain amyloid: ..beta..-(1-28), residues 1-28 of the ..beta.. protein; (Ala/sup 1 -/..beta..-(1-28), ..beta..-(1-28) with alanine substituted for lysine at position 16; and ..beta..-(18-28), residues 18-28 of the ..beta.. protein. ..beta..-(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-..beta..-conformation. (Ala/sup 16/)..beta..-(1-28) formed ..beta..-pleated sheet assemblies that were dissimilar to in vivo fibrils. The width of the 10-A spacing indicated stacks of about six sheets. Thus, substitution of the uncharged alanine for the positively charged lysine in the ..beta..-strand region enhances the packing of the sheets and dramatically alters the type of macromolecular aggregate formed. BETA-(18-28) formed assemblies that had even a greater number of stacked sheets. The findings on these homologous synthetic assemblies help to define the specific sequence that is required tomore »« less

Authors:: Kirschner, D A; Inouye, H; Duffy, L K; Sinclair, A; Lind, M; Selkoe, D J

Publication Date:: Thu Oct 01 00:00:00 EDT 1987

Research Org.:: Children's Hospital, Boston, MA (USA)

OSTI Identifier:: 7131292

Resource Type:: Journal Article

Journal Name:: Proc. Natl. Acad. Sci. U.S.A.; (United States)

Additional Journal Information:: Journal Volume: 84:19

Country of Publication:: United States

Language:: English

Subject:: 62 RADIOLOGY AND NUCLEAR MEDICINE; NERVOUS SYSTEM DISEASES; PATHOGENESIS; PROTEINS; CONFORMATIONAL CHANGES; X-RAY DIFFRACTION; ALANINES; HISTOLOGY; LYSINE; PATIENTS; PEPTIDES; STRUCTURAL MODELS; TRANSMISSION ELECTRON MICROSCOPY; AMINO ACIDS; CARBOXYLIC ACIDS; COHERENT SCATTERING; DIFFRACTION; DISEASES; ELECTRON MICROSCOPY; MICROSCOPY; ORGANIC ACIDS; ORGANIC COMPOUNDS; SCATTERING; 550602* - Medicine- External Radiation in Diagnostics- (1980-)

Citation Formats


                    Kirschner, D A, Inouye, H, Duffy, L K, Sinclair, A, Lind, M, and Selkoe, D J. Synthetic peptide homologous to. beta. protein from Alzheimer's disease forms amyloid-like fibrils in vitro.  United States: N. p., 1987. 
        Web.  doi:10.1073/pnas.84.19.6953.

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                    Kirschner, D A, Inouye, H, Duffy, L K, Sinclair, A, Lind, M, & Selkoe, D J. Synthetic peptide homologous to. beta. protein from Alzheimer's disease forms amyloid-like fibrils in vitro.  United States.  https://doi.org/10.1073/pnas.84.19.6953

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                    Kirschner, D A, Inouye, H, Duffy, L K, Sinclair, A, Lind, M, and Selkoe, D J. 1987.  
        "Synthetic peptide homologous to. beta. protein from Alzheimer's disease forms amyloid-like fibrils in vitro".  United States.  https://doi.org/10.1073/pnas.84.19.6953.

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@article{osti_7131292,

  title        = {Synthetic peptide homologous to. beta. protein from Alzheimer's disease forms amyloid-like fibrils in vitro},

  author       = {Kirschner, D A and Inouye, H and Duffy, L K and Sinclair, A and Lind, M and Selkoe, D J},

  abstractNote = {Progressive amyloid deposition in senile plaques and cortical blood vessels may play a central role in the pathogenesis of Alzheimer's disease. The authors 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 ..beta.. protein of brain amyloid: ..beta..-(1-28), residues 1-28 of the ..beta.. protein; (Ala/sup 1 -/..beta..-(1-28), ..beta..-(1-28) with alanine substituted for lysine at position 16; and ..beta..-(18-28), residues 18-28 of the ..beta.. protein. ..beta..-(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-..beta..-conformation. (Ala/sup 16/)..beta..-(1-28) formed ..beta..-pleated sheet assemblies that were dissimilar to in vivo fibrils. The width of the 10-A spacing indicated stacks of about six sheets. Thus, substitution of the uncharged alanine for the positively charged lysine in the ..beta..-strand region enhances the packing of the sheets and dramatically alters the type of macromolecular aggregate formed. BETA-(18-28) formed assemblies that had even a greater number of stacked sheets. The findings on these homologous synthetic assemblies help to define the specific sequence that is required to form Alzheimer's-type amyloid fibrils, thus providing an in vitro model of age-related cerebral amyloidogenesis.},

  doi          = {10.1073/pnas.84.19.6953},

  url          = {https://www.osti.gov/biblio/7131292},
  journal      = {Proc. Natl. Acad. Sci. U.S.A.; (United States)},
number       = ,

  volume       = 84:19,

  place        = {United States},

  year         = {Thu Oct 01 00:00:00 EDT 1987},

  month        = {Thu Oct 01 00:00:00 EDT 1987}

}

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