Abstract Tau phosphorylation and aggregation is the final common pathway for neuronal toxicity across multiple neurodegenerative diseases including Alzheimer disease, progressive supranuclear palsy, and corticobasal degeneration. We have previously shown that the fetal brain expresses high levels of phosphorylated tau, and even tau aggregates, without apparent toxic effects. The mechanisms for this remarkable resilience, however, remain unclear. In order to identify potential mediators of this resilience, we used bead-linked total tau immunoprecipitation in human fetal, adult, and Alzheimer disease brains. We then used heterologous transfection in HEK 293T cells followed by coimmunoprecipitation, mass photometry, and nuclear magnetic resonance (NMR) to further characterize the interaction of tau with one of our top hits, 14-3-3-β. We found significant differences between the tau interactome in fetal and AD brain, with little difference between adult and AD. There were significant differences in tau interaction with 14-3-3 family proteins between fetal and AD brain. We then determined that the 14-3-3 isoform with the highest difference, 14-3-3-β, preferentially interacts with 4R tau in vitro , forming a complex consisting of two 14-3-3-β, and one tau molecule. NMR studies using 15 N-labeled phosphorylated tau showed that the binding site for 14-3-3 was in the microtubule binding region of tau, which is truncated in 3R tau through the exclusion of exon 10. Our findings suggest that there are marked differences between the phospho-tau interactome in fetal and Alzheimer disease brain, including differences in interaction with the critical 14-3-3 family of protein chaperones, which may explain, in part, the resilience of fetal brain to tau toxicity.

Characterization of the Tau Interactome in Human Brain Reveals Isoform-Dependent Interaction with 14-3-3 Family Proteins