For the first time, natural Aβ fibrils (WT) implicated in Alzheimer's disease, as well as two synthetic mutants forming less toxic amyloid fibrils (L34T) and highly toxic oligomers (oG37C), are chemically characterized at the scale of a single structure using tip-enhanced Raman spectroscopy (TERS). While the proportion of TERS features associated with amino acid residues is similar for the three peptides, a careful examination of amide I and amide III bands allows us to clearly distinguish WT and L34T fibers organized in parallel β-sheets from the small and more toxic oG37C oligomers organized in anti-parallel β-sheets.

Click chemistry is widely used in materials and surface science for its high efficiency, ease of use and high yields. Azide-terminated SAMs have been prepared successfully by using three different deposition methods (postfunctionalization and direct grafting by immersion as well as spin coating). Strikingly, our study shows that the reactivity of the azido group on the surface with the alkyne in solution is not trivial and seems to be closely related to the orientation of the azide. Indeed, more the azide is vertically oriented more it is accessible and reactive. The orientation of azido dipoles at the surface depends strongly on the method used to prepare the monolayer. The post-functionalization method allows to have a homogeneous population of the azide groups on the surface with a better vertical orientation than that obtained using direct grafting by immersion or spin coating processes. Whatever the type of azide-terminated SAMs, the reactivity of the accessible vertical azido groups is complete. This study clearly demonstrates that it is possible to control the amount of reactive azides and, consequently, the amount of molecules immobilized on the surface after the click reaction by choosing the deposition method.