Resolving single-amyloid polymorphism in neurodegeneration via micro-to-nano analytical imaging and spectroscopy.

By 2050, one billion people worldwide will be affected by human diseases related to malfunctioning protein amyloids, such as neurodegeneration. Yet, the relationship between amyloids and disease is unclear; in turn, there are no effective treatments or cures. This knowledge gap is largely related to technological limits in characterising heterogeneous and nanoscale-sized amyloids and unravelling how their polymorphic properties are critical for cellular toxicity. Here, we review the latest advances in nano-imaging and nano-chemical spectroscopy in unravelling amyloid polymorphism from the single-molecule level to their analysis in cells and tissue. We introduce the concept of amyloid chemical polymorphism, beyond classical strains and polymorphism at the morphological level, as a key feature linking their properties to toxicity.