Conformational characterization of native and L17A/F19A-substituted dutch-typeβ-amyloid peptides

Some mutations which occur in the α/β-discordant region (resides 15 to 23) of β-amyloid peptide (Aβ) lead to familial Alzheimer’s disease (FAD). In vitro studies have shown that these genetic mutations could accelerate Aβaggregation. We recently showed that mutations in this region could alter the structural propensity, resulting in a different aggregative propensity of Aβ. Whether these genetic mutations display similar effects remains largely unknown. Here, we characterized the structural propensity and aggregation kinetics of Dutch-type Aβ₄₀ (Aβ₄₀(E22Q)) and its L17A/F19A-substituted mutant (Aβ₄₀(L17A/F19A/E22Q)) using circular dichroism spectroscopy, nuclear magnetic spectroscopy, and thioflavin T fluorescence assay. In comparison with wild-type Aβ₄₀, we found that Dutch-type mutation, unlikeArtic-typemutation(E22G),doesnot reduce theα-helicalpropensity of theα/β-discordant region in sodium dodecyl sulfate micellar solution. Moreover, we found that Aβ₄₀(L17A/F19A/E22Q) displays a higher α-helical propensity of the α/β-discordant region and a slower aggregation rate than Aβ₄₀(E22Q), suggesting that the inhibition of aggregationmight be via increasing the α-helical propensity of the α/β-discordant region, similar to that observed in wild-type and Artic-type Aβ₄₀. Taken together, Dutch-type and Artic-type mutations adopt different mechanisms to promote Aβaggregation, however, the L17A/F19A mutation could increase the α-helical propensities of both Dutch-type and Artic-type Aβ₄₀ and inhibit their aggregation.