Quantitative Methods for the Detection of Tau Seeding Activity in Human Biofluids.

Aurelien Lathuiliere,Bradley T Hyman

doi:10.3389/fnins.2021.654176

Aurelien Lathuiliere, Bradley T Hyman

Open Access

https://doi.org/10.3389/fnins.2021.654176

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Abstract

The ability of tau aggregates to recruit and misfold monomeric tau and propagate across brain regions has been studied extensively and is now recognized as a critical pathological step in Alzheimer’s disease (AD) and other tauopathies. Recent evidence suggests that the detection of tau seeds in human samples may be relevant and correlate with clinical data. Here, we review the available methods for the measurement of such tau seeds, their limitations and their potential implementation for the development of the next-generation biomarkers.

Highlights

The accumulation and deposition of tau protein aggregates in the human brain is a hallmark of Alzheimer’s disease (AD) and other tauopathies
The aggregation of recombinant tau into paired helical filaments is accelerated by the addition of pre-formed seeds, suggesting a seeded nucleation process that results in the elongation of aggregates (Friedhoff et al, 1998; von Bergen et al, 2000)
The critical role of tau seeding and spreading in the pathogenesis of AD is further supported by the stereotypical progression of tau pathology across brain regions that has been described by neuropathological studies (Braak and Braak, 1991) and confirmed more recently by molecular imaging studies (Cho et al, 2016; Scholl et al, 2016; Schwarz et al, 2016)

Summary

INTRODUCTION

The accumulation and deposition of tau protein aggregates in the human brain is a hallmark of Alzheimer’s disease (AD) and other tauopathies. Seed-competent tau is detected in the synaptic compartment in brain regions along the Braak staging before the appearance of the pathology (Holmes et al, 2014; DeVos et al, 2018). This soluble seed-competent species represent a small percentage of total tau that elutes as a high molecular weight (>∼300,000) fraction from a size exclusion chromatography column (Takeda et al, 2015, 2016). Plasma p-tau181 seemed to correlate with CSF p-tau181 and tau burden on PET imaging (Janelidze et al, 2020) These promising results need to be confirmed in larger primary care cohorts to validate the feasibility and clinical utility of this new biomarker

CEREBROSPINAL FLUID BIOCHEMICAL ASSAYS

SEED AMPLIFICATION ASSAYS

IN VIVO SEED AMPLIFICATION ASSAYS

DISCUSSION AND FUTURE