Oligomeric tau enters brain vascular endothelial cells and induces cellular senescence and brain microvascular dysfunction in tauopathy

Abstract

AbstractBackgroundVascular mechanisms of Alzheimer’s disease (AD) may constitute the most therapeutically addressable biological pathway underlying dementia. Soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, particularly in microvascular endothelial cells.MethodsPrimary human brain microvascular endothelial cells (HBEC) were exposed to tau oligomers. Microtubule stability, eNOS activation, and markers of senescence were measured. Mice expressing P301S‐mutant human tau (P301S(PS19) mice), a model of tauopathy, were given immunotherapy to selectively remove tau oligomers, or non‐specific IgGs. After measurements of vascular reactivity, eNOS activity and markers of senescence were measured in microvasculature purified from brain.ResultOligomeric tau significantly decreased microtubule stability and eNOS activity, and induced cellular senescence in primary HBECs. Microtubule destabilization, reduced eNOS activity, and increased markers of cellular senescence in brain microvasculature of P301S(PS19) mice were associated with impaired vascular reactivity, and the latter was negated by immunotherapy that specifically removed oligomeric tau from brain.ConclusionBrain microvascular deficits in P301S(PS19) mice modeling tauopathy, mediated by tau oligomers, may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of tau oligomers. Pathogenic tau oligomers and senescent brain microvascular endothelial cells may thus be targets for intervention in AD and other tauopathies.