Temperature-dependent β-sheet formation in β-amyloid Aβ1–40 peptide in water: uncoupling β-structure folding from aggregation

To probe the role of temperature in the conversion of soluble Alzheimer’s β-amyloid peptide (Aβ) to insoluble β-sheet rich aggregates, we analyzed the solution conformation of Aβ1–40 from 0 to 98°C by far-UV circular dichroism (CD) and native gel electrophoresis. The CD spectra of 15–300 μg/ml Aβ1–40 in aqueous solution (pH∼4.6) at 0°C are concentration-independent and suggest a substantially unfolded and/or unusually folded conformation characteristic of Aβ monomer or dimer. Heating from 0 to 37°C induces a rapid reversible coil to β-strand transition that is independent of the peptide concentration and thus is not linked to oligomerization. Consequently, this transition may occur within the Aβ1–40 monomer or dimer. Incubation at 37°C leads to slow reversible concentration-dependent β-sheet accumulation; heating to 85°C induces further β-sheet folding and oligomerization. Our results demonstrate the importance of temperature and thermal history for the conformation of Aβ.