Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature.

The accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary inositol 1,4,5-triphosphate receptor (IP 3 R)-mediated calcium (Ca 2+ ) signals to direct blood flow. The initiation and amplification of endothelial cell IP 3 R-mediated Ca 2+ signals requires an intact microtubule cytoskeleton. Since tau accumulation in endothelial cells disrupts native microtubule stability, we reasoned that tau-induced microtubule destabilization would impair endothelial IP 3 -evoked Ca 2+ signaling. We tested the hypothesis that tau disrupts the regulation of local cerebral blood flow by reducing endothelial cell Ca 2+ signals and endothelial-dependent vasodilation. We used a pathogenic soluble tau peptide (T-peptide) model of tau aggregation and mice with genetically encoded endothelial Ca 2+ sensors to measure cerebrovascular endothelial responses to tau exposure. T-peptide significantly attenuated endothelial Ca 2+ activity and cortical capillary blood flow in vivo . Further, T-peptide application in pressurized cerebral arteries rapidly inhibited endothelium-dependent vasodilation, but not vasodilation in response to an exogenous nitric oxide donor. This study demonstrates that pathogenic tau alters cerebrovascular function through direct attenuation of endothelial Ca 2+ signaling and endothelium-dependent vasodilation.