Structural dynamics of the ΔE22 (Osaka) familial Alzheimer’s disease-linked amyloid β-protein

Content Provider	Scilit
Author	Inayathullah, Mohammed Teplow, David B.
Copyright Year	2011
Description	Journal: Amyloid 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.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396427/pdf https://www.tandfonline.com/doi/pdf/10.3109/13506129.2011.580399
ISSN	13506129
e-ISSN	17442818
DOI	10.3109/13506129.2011.580399
Journal	Amyloid
Issue Number	3
Volume Number	18
Language	English
Publisher	Informa UK Limited
Publisher Date	2011-06-13
Access Restriction	Open
Subject Keyword	Journal: Amyloid Alzheimer's Disease Amyloid Β-protein Osaka Mutation Fibril Formation Oligomerization
Content Type	Text
Subject	Internal Medicine