Tip Enhanced Raman Spectroscopy Study of Amyloid Superstructures

Aggregation processes of aberrant proteins leading to the formation of amyloid oligomers and fibrils are considered primarily responsible for promoting synaptic failure and neuronal death associated with neurological disorders such as Alzheimer's and Parkinson's diseases [1]. Unravelling the relationship between structure and neurotoxicity of protein oligomers appears pivotal in understanding the causes of the pathological process, as well as in designing novel diagnostic and therapeutic strategies tuned toward the earliest and pre-symptomatic stages of the disease. In this work we show how to benefit from Tip Enhanced Raman spectroscopy (TERS) as a surface-sensitive tool with spatial resolution on the nanoscale, to inspect the spatial organization and surface character of individual protein oligomers. Our TERS investigation provides compelling evidence of the presence of chemostructural determinants in the case of toxic oligomers, which sheds new light on the mechanism by which they cause cellular impairment. Specifically, we identified specific aminoacid residues that appear exposed on the surface of toxic oligomers while buried in the non-toxic forms, with obvious implications for the elucidation of the structural factors responsible for cell toxicity at the single residue level [2]. These residues, thanks to their outward disposition, might represent structural factors driving the pathogenic behavior exhibited by protein misfolded oligomers, including affecting cell membrane integrity and specific signaling pathways in neurodegenerative conditions.