Cofactor-Free Serial Amplification of Tau Filaments from Alzheimer’s Disease and Other Tauopathies Depends on the Conformational State of Tau Monomers

TL;DR

This study shows that Tau filaments in Alzheimer’s disease and other tauopathies can grow without cofactors, depending on the shape of individual Tau proteins.

Contribution

The study reveals that cofactor-free amplification of Tau filaments depends on the conformational state of Tau monomers.

Findings

AD Tau filaments can recruit Tau monomers without cofactors at low salt concentrations.

PSP and PiD Tau filaments can also be amplified without cofactors, retaining their cross-seeding properties.

The conformational state of Tau monomers determines whether filament propagation occurs.

Abstract

Tau filaments are
a defining characteristic of Alzheimer’s
disease (AD) and numerous other neurodegenerative disorders. The deposition
of Tau protein into aggregates involves templated recruitment of Tau
monomers onto the filament ends via their microtubule-binding repeats.
This structural conversion is central to the propagation of Tau pathology,
yet its molecular mechanisms are still poorly understood. Specifically,
it is unclear whether cofactors are required for templated growth.
To gain insights into this process, we probed the serial amplification
of pathological Tau filaments from AD, Pick’s disease (PiD),
and progressive supranuclear palsy (PSP). These filaments are made
from different compositions of three- and four-repeat (3R and 4R)
Tau. We observe that AD Tau filaments recruit full-length 3R and 4R
Tau in the absence of cofactors at low salt concentration but not
at physiological salt concentration and that these filaments can be
independently amplified over multiple generations. PiD Tau and PSP
Tau filaments can be similarly amplified. The generated filaments
retain the cross-seeding properties of the pathological seeds; PSP
filaments recruit only 4R Tau, PiD filaments recruit only 3R Tau,
and AD filaments recruit both. Regardless of the structural fidelity
of the amplification process, we show that the Tau monomer ensemble
serves as an entry point for templated growth and that the conformational
state of this ensemble (expanded versus compact) determines whether
propagation occurs.

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