Abstract:

Tau aggregation into amyloid fibrils is linked to the development of neurodegenerativediseases, including Alzheimer’s disease (AD). The molecular processes driving aggre-gation in disease are still being uncovered, highlighting the need for innovative toolsto study aggregation reactions. Here, we introduce FibrilPaint1 as a tool to measurethe size of Tau amyloid fibrils in fluids, from early aggregation stages to mature fibrils.FibrilPaint1 is a 22mer peptide with exciting properties: i) FibrilPaint1 binds fibrilswith nanomolar affinity; ii) it also binds to precursors, down to a size of only 4 layers;iii) it does not bind to monomers; iv) it is fluorescently labeled, which allows monitor-ing and localizing interactions; v) FibrilPaint1 recognizes various Tau fibrils, includingpatient- derived fibrils from AD, corticobasal degeneration (CBD), and frontotemporaldementia (FTD); vi) it also binds to fibrils from amyloids derived from Amyloid- β,α- synuclein, and huntingtin vii) FibrilPaint1 is selective for the amyloid state and doesnot have background binding to amorphous aggregates, blood serum, or cell lysate. Incombination with flow- induced dispersion analysis (FIDA), a microfluidics technology,we determined the molecular size of amyloid fibrils with submicroliter sample volumes.This setup acts as a molecular ruler at layer resolution—we determined Tau fibril lengthfrom 4 to 1100 layers in solution. This is an interesting parameter for molecular studiesin dementia, with potential for diagnostic applications.