title: Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy.
abstract: BACKGROUND
  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.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Blair
authors.forename: Haley D
authors.initials: HD
authors.lastname: Frauen
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Nordhues
authors.forename: Sara
authors.initials: S
authors.lastname: Bijan
authors.forename: Yen-Chi
authors.initials: YC
authors.lastname: Lin
authors.forename: Frank
authors.initials: F
authors.lastname: Zamudio
authors.forename: Lidice D
authors.initials: LD
authors.lastname: Hernandez
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Sabbagh
authors.forename: Maj-Linda B
authors.initials: ML
authors.lastname: Selenica
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D004912:Erythrocytes / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D008137:Longitudinal Studies; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000473:pathology; D024801:Tauopathies / Q000473:pathology*; D016875:tau Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D015703:Antigens, CD; D005904:Glial Fibrillary Acidic Protein; D055551:HSP27 Heat-Shock Proteins; D007074:Immunoglobulin G; D016875:tau Proteins; D004318:Doxycycline