Mechanisms of Heparin-Induced Tau Aggregation Revealed by a Single Nanopore

Abstract

Protein aggregation is involved in many diseases, including Parkinson's and Alzheimer's. The latter is characterized by intraneuronal deposition of amyloid aggregates composed of the tau protein. Although large and insoluble aggregates are typically found in affected brains, intermediate soluble oligomers are thought to represent crucial species for toxicity and spreading. Nanopore sensors constitute an emerging technology that allows the detection of the size and populations of molecular assembly present in a sample. Here, we employed conical nanopores to obtain the particle distributions during tau aggregation. We identified three distinct populations, monomers, oligomers, and fibrils, which we could quantify along the aggregation process. By comparing tau wild type with a mutant carrying the disease-associated P301L mutation, we showed that the latter mutation promotes the formation of oligomers. We furthermore highlighted that the P301L mutation promotes fibril breakage. This work demonstrates that conical nanopore is a powerful tool to measure and quantify transient protein aggregate intermediates.