Chemotherapy-induced cognitive impairment ("chemobrain") is a frequent side-effect
in cancer survivors treated with paclitaxel (PTX). The mechanisms responsible for
PTX-induced cognitive impairment remain obscure, and there are no effective treatments
or prevention strategies. Here, we test the hypothesis that PTX induces endothelial
senescence, which impairs microvascular function and contributes to the genesis of
cognitive decline. We treated transgenic p16-3MR mice, which allows the detection
and selective elimination of senescent cells, with PTX (5 mg/kg/day, 2 cycles; 5 days/cycle).
PTX-treated and control mice were tested for spatial memory performance, neurovascular
coupling (NVC) responses (whisker-stimulation-induced increases in cerebral blood
flow), microvascular density, blood-brain barrier (BBB) permeability and the presence
of senescent endothelial cells (by flow cytometry and single-cell transcriptomics)
at 6 months post-treatment. PTX induced senescence in endothelial cells, which associated
with microvascular rarefaction, NVC dysfunction, BBB disruption, neuroinflammation,
and impaired performance on cognitive tasks. To establish a causal relationship between
PTX-induced senescence and impaired microvascular functions, senescent cells were
depleted from PTX-treated animals (at 3 months post-treatment) by genetic (ganciclovir)
or pharmacological (treatment with the senolytic drug ABT263/Navitoclax) means. In
PTX treated mice, both treatments effectively eliminated senescent endothelial cells,
rescued endothelium-mediated NVC responses and BBB integrity, increased capillarization
and improved cognitive performance. Our findings suggest that senolytic treatments
can be a promising strategy for preventing chemotherapy-induced cognitive impairment.
