In vitro tau aggregation inducer molecules influence the effects of MAPT mutations on aggregation dynamics

Abstract

AbstractAlzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRDs) affect 6 million Americans and they are projected to have an estimated health care cost of $355 billion for 2021. A histopathological hallmark of AD and many ADRDs is the aberrant intracellular accumulation of the microtubule associated protein tau. These neurodegenerative disorders that contain tau aggregates are collectively known as tauopathies and recent structural studies have shown that different tauopathies are characterized by different “strains” of tau filaments. In addition, mutations in the gene that encodes for tau protein expression have been associated with a group of tauopathies known as frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17 or familial frontotemporal dementia). In vitro studies often use small molecules to induce tau aggregation as tau is extremely soluble and does not spontaneously aggregate in typical lab conditions and the use of authentic filaments to conduct in vitro studies is not feasible. This study highlights how different inducer molecules can have fundamental disparities to how disease related mutations effect the aggregation dynamics of tau. Using three different classes of tau aggregation inducer molecules we characterized disease relevant mutations in tau’s PGGG motifs at positions P301S, P332S, and P364S. When comparing these mutations to wild type tau, we found that depending on the type of inducer molecule used we saw fundamental differences in total aggregation, aggregation kinetics, immunoreactivity, and filament morphology. These data support the hypothesis that different tau aggregation inducer molecules make different polymorphs and perhaps structurally distinct strains.