Single‐particle characterization of tau oligomers in solution

Abstract Background Protein aggregation is the hallmark of neurodegenerative disorders such as Alzheimer’s disease (AD), and oligomeric species of microtubule‐associated protein Tau are implicated as neurotoxic species as well as promising biomarkers. The size and shape of the oligomers are critical to their toxicity. Currently existing, sensitive immunoassays for biomarker detection do, however, not provide information on the size‐ or shape‐distribution of Tau aggregates. This limitation reduces the information content from tau analyses since specific sizes and shapes of oligomeric Tau aggregates are more toxic than others. Hence, a novel approach that reveals the size‐, and the shape‐distribution of Tau oligomers rapidly in solution would be ideal. Method Here, we use resistive‐pulse sensing with solid‐state nanopores to detect and characterize Tau oligomers on a single particle basis in solution with respect to their size and shape. Result The nanopore‐based approach facilitates single‐particle detection and fingerprinting of tau oligomers with regard to their size and shapes. We can determine the heterogeneity among oligomers with respect to their sizes and shapes, which is usually overlooked by averaging. We follow and compare the aggregation kinetics of wild type and AD‐associated variants of Tau. Conclusion Resistive‐pulse sensing using nanopores allows rapid fingerprinting Tau oligomers in solution in a label‐free manner. The size and shape information of oligomeric species can improve the general understanding of their toxicity and facilitate the development of new prevention strategies.