The α‐to‐β Conformational Transition of Alzheimer's Aβ‐(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding

Abstract

Current views of the role of beta-amyloid (Abeta) peptide fibrils range from regarding them as the cause of Alzheimer's pathology to having a protective function. In the last few years, it has also been suggested that soluble oligomers might be the most important toxic species. In all cases, the study of the conformational properties of Abeta peptides in soluble form constitutes a basic approach to the design of molecules with "antiamyloid" activity. We have experimentally investigated the conformational path that can lead the Abeta-(1-42) peptide from the native state, which is represented by an alpha helix embedded in the membrane, to the final state in the amyloid fibrils, which is characterized by beta-sheet structures. The conformational steps were monitored by using CD and NMR spectroscopy in media of varying polarities. This was achieved by changing the composition of water and hexafluoroisopropanol (HFIP). In the presence of HFIP, beta conformations can be observed in solutions that have very high water content (up to 99 % water; v/v). These can be turned back to alpha helices simply by adding the appropriate amount of HFIP. The transition of Abeta-(1-42) from alpha to beta conformations occurs when the amount of water is higher than 80 % (v/v). The NMR structure solved in HFIP/H2O with high water content showed that, on going from very apolar to polar environments, the long N-terminal helix is essentially retained, whereas the shorter C-terminal helix is lost. The complete conformational path was investigated in detail with the aid of molecular-dynamics simulations in explicit solvent, which led to the localization of residues that might seed beta conformations. The structures obtained might help to find regions that are more affected by environmental conditions in vivo. This could in turn aid the design of molecules able to inhibit fibril deposition or revert oligomerization processes.

Exploring the aggregation free energy landscape of the amyloid-β protein (1–40)

“…The hairpin structure has also previously been observed in all-atom simulations of Aβ40 (17) and Aβ42 (17,18). In vitro, these two structural classes are of similar stability as witnessed by there being a reversible α to β conformational transition in monomeric Aβ42, which occurs on changing the polarity of the solvent (19). In our simulations of the higher oligomers, as shown in the dimer (II) and trimer (III) cases in Fig.…”

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

“…Moreover, their secondary structure seems to depend on the environmental conditions. In its native state, Ab is supposed to adopt an a-helix structure embedded in the membrane, just after APP cleavage by secretases [43]. Lately, a high resolution structure of Ab monomers in solution stabilized by a phage-display selected Affibody Ò protein showed a b-hairpin structure implicating two short b-strands (aa 17-23 and aa [30][31][32][33][34][35][36] in an antiparallel organization [40].…”

The Structures of the E22Δ Mutant-Type Amyloid-β Alloforms and the Impact of E22Δ Mutation on the Structures of the Wild-Type Amyloid-β Alloforms

“…50 Following our recent studies, the initial structure of the wild-type Aβ42 monomer was taken from NMR measurements. 51 The E22Δ mutant-type Aβ42 initial structure was created by removing the Glu22 amino acid and connecting residues Ala21 and Asp23. Removing the last two residues (Ile41 and Ala42) from the wild-and E22Δ mutant-type Aβ42 resulted in the initial geometries of the wild-and E22Δ mutant-type Aβ40, respectively.…”