Pathogenic Tau Drives Cellular Senescence in the Aging Brain

Evidence suggests a multidirectional relationship between cellular senescence, chronic inflammation, and toxic tau aggregation in the aging brain. Inflammation is well known to be associated with the onset and progression of neurodegenerative conditions, and lingering senescent cells present throughout the aging body provide a significant contribution to chronic, unresolved inflammatory signaling. Clearing senescent cells in animal models of neurogeneration has been shown to reduce both inflammation and tau aggregation. Here, researchers show that the presence of pathogenic forms of tau protein can provoke cellular senescence and forms of vascular dysfunction in the brain. It is rarely the case that a damaging mechanism of aging stands on its own; it usually makes other damaging mechanisms worse in addition to causing its own direct consequences.

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.

Microvascular impairments in P301S(PS19) mice were partially negated by selective removal of pathogenic soluble tau aggregates from the brain. We found that similar to trans-neuronal transmission of pathogenic forms of tau, soluble tau aggregates are internalized by brain microvascular endothelial cells in a heparin-sensitive manner and induce microtubule destabilization, block endothelial nitric oxide synthase (eNOS) activation, and potently induce endothelial cell senescence that was recapitulated in vivo in microvasculature of P301S(PS19) mice.

Our studies suggest that soluble pathogenic tau aggregates mediate AD-like brain microvascular deficits in a mouse model of tauopathy, which may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of soluble tau aggregates.


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