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

Stacy A. Hussong, Andy Q. Banh, Candice E. Skike, Angela O. Dorigatti, Stephen F. Hernandez, Matthew J. Hart, Beatriz Ferran, Haneen Makhlouf, Maria Gaczynska, Pawel A. Osmulski, Salome A. McAllen, Kelly T. Dineley, Zoltan Ungvari, Viviana I. Perez, Rakez Kayed and Veronica Galvan ()
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Stacy A. Hussong: University of Oklahoma Health Sciences Center
Andy Q. Banh: University of Texas Health San Antonio
Candice E. Skike: University of Texas Health San Antonio
Angela O. Dorigatti: University of Texas Health San Antonio
Stephen F. Hernandez: University of Texas Health San Antonio
Matthew J. Hart: University of Oklahoma Health Sciences Center
Beatriz Ferran: University of Oklahoma Health Sciences Center
Haneen Makhlouf: University of Oklahoma Health Sciences Center
Maria Gaczynska: University of Texas Health San Antonio
Pawel A. Osmulski: University of Texas Health San Antonio
Salome A. McAllen: University of Texas Medical Branch at Galveston
Kelly T. Dineley: University of Texas Medical Branch at Galveston
Zoltan Ungvari: University of Oklahoma Health Sciences Center
Viviana I. Perez: Hevolution Foundation, 5.08
Rakez Kayed: University of Texas Medical Branch at Galveston
Veronica Galvan: University of Oklahoma Health Sciences Center

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37840-y

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