Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau

Insoluble fibrillar tau, the primary constituent of neurofibrillary tangles, has traditionally been thought to be the biologically active, toxic form of tau mediating neurodegeneration in Alzheimer's disease. More recent studies have implicated soluble oligomeric tau species, referred to as high molecular weight (HMW), due to their properties on size-exclusion chromatography, in tau propagation across neural systems. These two forms of tau have never been directly compared. We prepared sarkosyl-insoluble and HMW tau from the frontal cortex of Alzheimer patients and compared their properties using a variety of biophysical and bioactivity assays. Sarkosyl-insoluble fibrillar tau comprises abundant paired-helical filaments (PHF) as quantified by electron microscopy (EM) and is more resistant to proteinase K, compared to HMW tau, which is mostly in an oligomeric form. Sarkosyl-insoluble and HMW tau are nearly equivalent in potency in HEK cell bioactivity assay for seeding aggregates, and their injection reveals similar local uptake into hippocampal neurons in PS19 Tau transgenic mice. However, the HMW preparation appears to be far more potent in inducing a glial response including Clec7a-positive rod microglia in the absence of neurodegeneration or synapse loss and promotes more rapid propagation of misfolded tau to distal, anatomically connected regions, such as entorhinal and perirhinal cortices. These data suggest that soluble HMW tau has similar properties to fibrillar sarkosyl-insoluble tau with regard to tau seeding potential, but may be equal or even more bioactive with respect to propagation across neural systems and activation of glial responses, both relevant to tau-related Alzheimer phenotypes.

Automated summary

Insoluble fibrillar tau has long been considered the active form of tau in Alzheimer's disease, but recent studies have shown that soluble oligomeric tau may also play a role in tau propagation. In this study, we compared the properties of insoluble fibrillar tau and soluble high molecular weight (HMW) tau from Alzheimer patients. We found that both forms of tau are potent in seeding tau aggregates, but HMW tau appears to be more effective in inducing glial responses and promoting the spread of misfolded tau to other brain regions. These findings suggest that HMW tau may be more bioactive in tau-related Alzheimer phenotypes.