Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy

Laura J. Blair, Haley D. Frauen, Bo Zhang, Bryce A. Nordhues, Sara Bijan, Yen Chi Lin, Frank Zamudio, Lidice D. Hernandez, Jonathan J. Sabbagh, Maj Linda B. Selenica, Chad A. Dickey

Research output: Contribution to journalArticlepeer-review

138 Scopus citations

Abstract

INTRODUCTION: The blood-brain barrier (BBB) is damaged in tauopathies, including progressive supranuclear palsy (PSP) and Alzheimer's disease (AD), which is thought to contribute to pathogenesis later in the disease course. In AD, BBB dysfunction has been associated with amyloid beta (Aß) pathology, but the role of tau in this process is not well characterized. Since increased BBB permeability is found in tauopathies without Aß pathology, like PSP, we suspected that tau accumulation alone could not only be sufficient, but even more important than Aß for BBB damage.

RESULTS: Longitudinal evaluation of brain tissue from the tetracycline-regulatable rTg4510 tau transgenic mouse model showed progressive IgG, T cell and red blood cell infiltration. The Evans blue (EB) dye that is excluded from the brain when the BBB is intact also permeated the brains of rTg4510 mice following peripheral administration, indicative of a bonafide BBB defect, but this was only evident later in life. Thus, despite the marked brain atrophy and inflammation that occurs earlier in this model, BBB integrity is maintained. Interestingly, BBB dysfunction emerged at the same time that perivascular tau emerged around major hippocampal blood vessels. However, when tau expression was suppressed using doxycycline, BBB integrity was preserved, suggesting that the BBB can be stabilized in a tauopathic brain by reducing tau levels.

CONCLUSIONS: For the first time, these data demonstrate that tau alone can initiate breakdown of the BBB, but the BBB is remarkably resilient, maintaining its integrity in the face of marked brain atrophy, neuroinflammation and toxic tau accumulation. Moreover, the BBB can recover integrity when tau levels are reduced. Thus, late stage interventions targeting tau may slow the vascular contributions to cognitive impairment and dementia that occur in tauopathies.

Original languageEnglish
Pages (from-to)8
Number of pages1
JournalActa neuropathologica communications
Volume3
DOIs
StatePublished - Jan 31 2015

Bibliographical note

Funding Information:
This material is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital under merit review award BX001637. The contents of this publication do not represent the views of the Department of Veterans Affairs or the United States Government. This work was also supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke R01 NS073899. We would like to thank Dr. Beyong “Jake” Cha and the USF Lisa Muma Weitz Imaging Core for the use of the Leica SP2 confocal microscope.

Funding

This material is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital under merit review award BX001637. The contents of this publication do not represent the views of the Department of Veterans Affairs or the United States Government. This work was also supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke R01 NS073899. We would like to thank Dr. Beyong “Jake” Cha and the USF Lisa Muma Weitz Imaging Core for the use of the Leica SP2 confocal microscope.

FundersFunder number
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council
U.S. Department of Veterans AffairsI01 BX001637
National Institutes of Health (NIH)
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke CouncilR01NS073899

    ASJC Scopus subject areas

    • Pathology and Forensic Medicine
    • Clinical Neurology
    • Cellular and Molecular Neuroscience

    Fingerprint

    Dive into the research topics of 'Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy'. Together they form a unique fingerprint.

    Cite this