Vascular tau in AD
Cerebromicrovascular dysfunction has a critical role in cognitive decline associated with Alzheimer’s disease (AD). We recently showed that prefilamentous aggregates of hyper-phosphorylated tau (tau oligomers) accumulate in brain microvasculature in AD, in progressive supranuclear palsy, in mouse models of AD, and in brains of ‘pure’ tauopathy models. Further, we found that expression of human tau in a tau transgenic model was sufficient to induce profound cerebromicrovascular dysfunction.
Levels of extracellular tau in human brain are comparable or higher than those of amyloid-beta (Aß). Like Aß, neuronally-originated tau oligomers released in the extracellular space can reach nearby vascular elements. We have shown that extracellular misfolded tau can enter endothelial cells and induce endogenous tau phosphorylation and aggregation, leading to microtubule destabilization and decreased activation of endothelial nitric oxide synthase. How misfolded extracellular tau accumulates in cerebrovasculature and how this process impacts cerebrovascular function, however, is still unknown. The goal of this project, in collaboration with the laboratories of Drs. Rakez Kayed and Kelly Dineley, is to define the mechanisms by which brain microvascular tau accumulation contributes to brain vascular dysfunction in AD, and determine the potential for misfolded tau clearance through immunotherapy as a novel intervention for cerebrovascular dysfunction in AD.