Single particle mass photometry provides size distributions of tau oligomers in CSF samples revealing strong differences between samples from Alzheimer’s patients and healthy controls

Abstract

AbstractBackgroundTau oligomers are considered toxic species in neurodegenerative disorders and their abundance correlate well with the disease onset and pathology. Assays used for detection of these toxic tau oligomer species fail to detect their low levels and to differentiate between various oligomers. This limitation reduces the potential for early diagnosis and for possible intervention. A label‐free approach that can detect these biomarkers at low concentrations while also revealing their size distribution will be ideal.MethodHere, we use a combination of tau oligomer‐specific immunoprecipitation from human CSF samples and single‐molecule mass analysis based on so‐called mass photometry to determine the size of thousands of individual oligomeric species in solution in a label‐free manner.ResultSingle‐oligomer mass analysis makes it possible to determine the number of tau monomers in thousands of individual oligomer particles in CSF samples from human patients and control subjects. The method reveals a dramatic difference in the size distribution of tau oligomer species from Alzheimer’s patients compared to control subjects. In particular, samples from AD patients contain a significant fraction of trimeric tau oligomers, which are completely absent in the control samples.ConclusionSingle‐particle mass analysis of tau protein oligomers enables discrimination of samples from patients with AD from those of age‐matched control subjects. Furthermore, single‐particle based analysis of the size distribution of oligomeric species will help to shed light on the toxicity of various oligomers species.