Research

Tau Prion Strains

Prions exhibit distinct “strains,” which are conformers that replicate faithfully in serial transmission between hosts, and produce predictable patterns of neuropathology. We previously determined that tau exhibits “strain-like” propagation patterns in vitro, in which one amyloid structure begets the same structure upon serial exposure to monomer.

This property also clearly manifests in cells and animals.

We have now created stable cell lines that indefinitely and faithfully propagate unique tau prion strains from mother to daughter cells. We discriminate these strains using biochemical and morphological parameters. When a tau prion is purified from one cell and introduced into a naïve cell, this recreates the same strain, proving that the tau amyloid structure itself encodes all of the information required to establish unique patterns of disease biology. Indeed, when we introduce a tau prion strain isolated from a cell into a vulnerable animal, it produces strain-specific neuropathology that can be passaged between animals, and even back into the cultured cell system.

With the cell propagation system, we have isolated disease-associated strains from patient brains, and find disease-associated groups, or “clouds” of tau prions. This association implies that we should be able to diagnose patients based on the structural composition of their tau prion strains. To test their involvement in variation in neuropathology, including rate of spread through the brain and regional vulnerability, we have isolated and characterized 18 independent strains. Upon introduction into mice, each strain accounts for a completely distinct pattern of disease.

The identification of tau prion strains in patients and their characterization in mice now sets the stage to link specific tau prion structures with their biological effects: what structural features constitute a strain, how can we identify these structures in patients, and how do specific conformations lead to unique patterns of pathology?