Basic Science and Pathogenesis.

Background: Cellular senescence is defined as cell cycle arrest and the acquisition of a proinflammatory 'senescence-associated secretory phenotype' (SASP). In Alzheimer's disease (AD), tau protein in neurons undergoes hyperphosphorylation and misfolding, resulting in the formation of pathogenic soluble aggregates known as tau oligomers. Tau oligomers are released from neurons during neuronal activation and are transmitted to postsynaptic cells in a prion-like fashion.

Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy.

Vascular mechanisms of Alzheimer's disease (AD) may constitute a therapeutically addressable biological pathway underlying dementia. We previously demonstrated that soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, including prominently in microvascular endothelial cells. Here we show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy and drives AD-like brain microvascular deficits.