title: Structural dynamics of the ΔE22 (Osaka) familial Alzheimer's disease-linked amyloid β-protein.
abstract: A familial form of Alzheimer disease recently was described in a kindred in Osaka, Japan. This kindred possesses an amyloid β-protein (Aβ) precursor mutation within the Aβ coding region that results in the deletion of Glu22 (ΔE22). We report here results of studies of [ΔE22]Aβ40 and [ΔE22]Aβ42 that sought to elucidate the conformational dynamics, oligomerization behavior, fibril formation kinetics, fibril morphology, and fibril stability of these mutant peptides. Both [ΔE22]Aβ peptides had extraordinary β-sheet formation propensities. The [ΔE22]Aβ40 mutant formed β-sheet secondary structure elements ≈400-fold faster. Studies of β-sheet stability in the presence of fluorinated alcohol cosolvents or high pH revealed that the ΔE22 mutation substantially increased stability, producing a rank order of [ΔE22]Aβ42 >>Aβ42 > [ΔE22]Aβ40 > Aβ40. The mutation facilitated formation of oligomers by [ΔE22]Aβ42 (dodecamers and octadecamers) that were not observed with Aβ42. Both Aβ40 and Aβ42 peptides formed nebulous globular and small string-like structures immediately upon solvation from lyophilizates, whereas short protofibrillar and fibrillar structures were evident immediately in the ΔE22 samples. Determination of the critical concentration for fibril formation for the [ΔE22]Aβ peptides showed it to be ≈1/2 that of the wild type homologues, demonstrating that the mutations causes a modest increase in fibril stability. The magnitude of this increase, when considered in the context of the extraordinary increase in β-sheet propensity for the ΔE22 peptides, suggests that the primary biophysical effect of the mutation is to accelerate conformational changes in the peptide monomer that facilitate oligomerization and higher-order assembly.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, CA 90095, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Inayathullah
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)