1. Structural dynamics of the ΔE22 (Osaka) familial Alzheimer's disease-linked amyloid β-protein.
- Author
-
Inayathullah, Mohammed and Teplow, David B.
- Subjects
- *
ALZHEIMER'S disease , *AMYLOID beta-protein , *STRUCTURAL dynamics , *GENETIC mutation - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF