Understanding the modulators of tau amyloid aggregation pathways

Aggregation of the intrinsically disordered protein tau is a hallmark of several diseases, called
tauopathies, including Alzheimer’s disease. Amyloid aggregates are solid-like protein
assemblies that are highly ordered and stable. Strikingly, different aggregate structures are
involved in distinct tauopathies, revealing a structure-pathology relationship. Yet, the basic
mechanisms and factors that drive tau aggregation and structural differentiation remain
unknown.
Here we explore the modulators of tau aggregation. We intend to provide a unified view on
how factors such as disease-associated mutations, liquid-liquid phase separation and
interaction with molecular cofactors modulate tau aggregation. Using a range of biophysical
methods, including small angle X-ray scattering (SAXS) and electron paramagnetic resonance
spectroscopy (EPR), we investigate the driving forces of amyloid formation. Despite its
disordered nature, we show that the aggregation propensity of tau is encoded in its structure at
a monomer level. Furthermore, we decipher the mechanisms through which aggregation
inducers, such as lipids, modulate aggregation pathways to navigate between different forms
of tau amyloids. These results help to understand how different diseases-specific tau strains
can emerge and how they can be reconstituted in vitro.