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Abstract
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 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.
Brain microvascular dysfunction occurs in Alzheimer’s disease and other taupathies. Here the authors show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy, and that it contributes to vascular deficits in these mice.
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1 University of Oklahoma Health Sciences Center, Department of Biochemistry and Molecular Biology, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618); University of Oklahoma Health Sciences Center, Center for Geroscience and Healthy Brain Aging, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618); Oklahoma City Veterans Health Care System, Oklahoma City, USA (GRID:grid.266902.9)
2 University of Texas Health San Antonio, South Texas Medical Scientist Training Program, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); University of Texas Health San Antonio, Barshop Institute for Longevity and Aging Studies, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880)
3 University of Texas Health San Antonio, Barshop Institute for Longevity and Aging Studies, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880)
4 University of Oklahoma Health Sciences Center, Department of Biochemistry and Molecular Biology, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618); University of Oklahoma Health Sciences Center, Center for Geroscience and Healthy Brain Aging, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618); University of Oklahoma Health Sciences Center, Center for Therapeutic Science, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618)
5 University of Oklahoma Health Sciences Center, Department of Biochemistry and Molecular Biology, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618); University of Oklahoma Health Sciences Center, Center for Geroscience and Healthy Brain Aging, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618)
6 University of Texas Health San Antonio, Barshop Institute for Longevity and Aging Studies, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); University of Texas Health Science Center at San Antonio, Department of Molecular Medicine, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880)
7 University of Texas Medical Branch at Galveston, Departments of Neurology, Neuroscience and Cell Biology, Galveston, USA (GRID:grid.176731.5) (ISNI:0000 0001 1547 9964); University of Texas Medical Branch at Galveston, Mitchell Center for Neurodegenerative Disease, Galveston, USA (GRID:grid.176731.5) (ISNI:0000 0001 1547 9964); University of Texas Medical Branch at Galveston, Sealy Center for Vaccine Development, Galveston, USA (GRID:grid.176731.5) (ISNI:0000 0001 1547 9964)
8 University of Oklahoma Health Sciences Center, Center for Geroscience and Healthy Brain Aging, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618); University of Oklahoma Health Sciences Center, Department of Neurosurgery, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618); Semmelweis University, International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Budapest, Hungary (GRID:grid.11804.3c) (ISNI:0000 0001 0942 9821)
9 Hevolution Foundation, 5.08, Riyadh, Saudi Arabia (GRID:grid.11804.3c)