Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy
© Blair et al.; licensee BioMed central. 2015
Received: 6 January 2015
Accepted: 12 January 2015
Published: 31 January 2015
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.
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.
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.
KeywordsrTg4510 Alzheimer’s disease Blood-brain barrier Tau Vascular
The blood-brain barrier (BBB) is a physical barrier of endothelial cells, supported by astrocytes, that selectively limits the passage of peripheral blood components and pathogens into the brain, while allowing the passage of essential nutrients [1,2]. In aging, there is a decline in the stability of the BBB leading to increased permeability . This disruption of BBB integrity is exacerbated in Alzheimer’s disease (AD) [4-6], allowing peripheral immune cells access to the brain and perhaps exacerbating pathology by promoting detrimental neuroinflammation [7-10]. Most evidence suggests that this increase in BBB damage is driven by accumulation of amyloid-beta (Aß), particularly along the vasculature [11-13]. However, the microtubule associated protein tau has been shown to accumulate as puncta in perivascular spaces in sporadic AD with cerebral amyloid angiopathy (CAA) . BBB damage is also observed in tauopathies that lack Aß over-production [15-17], suggesting a role for tau in BBB damage [18-21], although this has yet to be proven.
We turned to the well-characterized tetracycline inducible rTg4510 mouse model to address the gaps in our knowledge about the role of tau in BBB damage. These mice exhibit a robust pathological profile, which includes tau tangle formation, neuroinflammation, neuronal loss and cognitive deficits [22-24]. Overall tau accumulation is detectable by 1 month of age, while insoluble tau, neurotoxicity, and atrophy, appear as early as 2.5 months of age . These pathologies progressively worsen and by 8.5 months of age, roughly 80% of neurons in the CA1 and dentate gyrus are lost [22,24-27]. Importantly, tau expression can be suppressed by doxycycline (DOX) administration in this model, a feature that can be exploited to determine whether pathophysiological consequences of tau expression can be halted. For example, tau suppression was previously found to rescue memory deficits and neuronal loss in this model, without affecting the accumulation of neurofibrillary tangles .
Thus, we used this model to determine if and when BBB integrity might be compromised, and whether this was caused by tau accumulation alone, by brain volume loss, or by some other pathology yet to be described. We also exploited the DOX-regulation of this model to determine if BBB damage was permanent, and whether specific features of the model were most closely linked to BBB dysfunction. We found that tau accumulation does eventually lead to BBB disruption, but there is an extremely high threshold of neuronal loss that the BBB can withstand before losing integrity. In fact, onset of BBB disruption was concomitant with the appearance of perivascular tau, suggesting a relationship between these two pathologies. BBB function was largely restored when tau was suppressed, even well after onset of BBB dysfunction. These data suggest that tau accumulation can disrupt BBB integrity and that BBB dysfunction coincides with the appearance of perivascular tau. These findings are important considerations for drug discovery efforts based on this model because they suggest that the vasculature can recover when tau levels are reduced, suggesting that late stage interventions targeting tau may be useful for slowing the vascular contributions to cognitive impairment and dementia that occur in tauopathies.
Materials and methods
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal handling and procedures were carried out in accordance with the University of South Florida’s Institutional Animal Care and Use Committee (IACUC) in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care International (AALAC) regulations.
Mouse colony and tissue processing
The rTg4510 colony was bred and maintained as previously described [22,23]. Mice were harvested at 1-, 3-, 6-, 9-, and 12-months old (N = 5-8 per genotype). At sacrifice, mice were perfused with 0.9% saline solution; brains were rapidly removed and fixed with 4% paraformaldehyde overnight. Following sucrose gradients up to 30%, tissue was sectioned using a sliding microtome at a thickness of 25 μm.
Doxycycline treatment procedure
In the DOX treated groups, 10.5- to 11-month old rTg4510 (N = 7) and wild-type (N = 7) mice were treated for ~5 weeks with DOX and harvested at 12-months old. When DOX treatment was started, mice were given 1.5 g/L DOX (Sigma Cat# 9891, St. Louis, MO;) in 4% sucrose water for 48 hours. After two days, DOX water was replaced by tap water and mice were fed a DOX diet containing 0.2 g/kg DOX (Harlan Cat# TD.00502, Indianapolis, IN) until sacrifice.
Intracardiac injection of Evans blue (EB)
Intracardiac injection of EB (Sigma) was performed on 6- (N = 7), 9- (N = 8), 12- (N = 8), and 12-month old DOX-treated (N = 7) rTg4510 and wild-type littermates as previously described , with slight modification. Mice were anesthetized by inhalation of precisely 2% isoflurane, to prevent variance of BBB opening due to isoflurane inhalation . While in dorsal recumbency, hair was removed from the injection site, the site was sterilized, and a percutaneous stick was made through the rib cage between the 4th and 5th intercostal space from the mouse’s left side. 20 mg/kg EB in sterile PBS was injected into the left ventricle at a rate of approximately 200 μL/min forty minutes before sacrifice. Tissue was harvested as describe above, including transcardiac perfusion to remove all blood from blood vessels.
Immunohistochemistry and immunofluorescence
Tissue was stained free floating as previously described  with minor modifications using antibodies directed against tau (H-150) (Santa Cruz, Dallas, Tx; 1:5000), heat shock protein 27 kDa (Hsp27; c-20) (Santa Cruz; 1:5000), Glial fibrillary acidic protein (GFAP; DAKO, Carpinteria, CA; 1:3000), CD3+ (AbD serotec, Raleigh, NC; 1:30,000), and CD4+ (AbD serotec; 1:30,000) with swine anti-goat IgG BIOT (1:200), goat anti-rabbit IgG BIOT (1:10,000), goat anti-mouse IgG BIOT (1:3000) and goat anti-rat IgG BIOT (1:1000) secondary antibodies (Southern Biotech, Birmingham, AL). Blood vessels were stained using DyLight 488 labeled Lycopersicon Esculetum (Tomato) Lectin (Vector Laboratories; Burlingame CA; 1:200). Fluorescently stained tissues were stained free-floating as previously described . Briefly, following permeabilization, tissue was incubated with tau (H-150; 1:1000) and/or Hsp27 (1:100) primary antibody overnight. Following PBS washes, tissue was incubated with Alexa Fluor 488 donkey anti-goat IgG (Invitrogen, Grand Island, NY; 1:1000) and/or Alexa Fluor 633 goat anti-rabbit IgG (Invitrogen; 1:1000) secondary antibody for 2 hours, followed by an overnight incubation with Tomato Lectin 488 (1:500). Brightfield tissue was mounted, dehydrated, and coverslipped using DPX (VWR, Atlanta, GA). Fluorescently stained tissue was mounted and then coverslipped using ProLong Gold Antifade Reagent (Invitrogen). Hematoxylin (Sigma) and eosin (Sigma) (H&E) staining was performed on mounted tissue as previously described  to view red blood cells (RBCs). Following nuclear and cytoplasmic staining, tissue was rapidly dehydrated in ethanol gradients, cleared in xylenes, and coverslipped using DPX.
Tissue imaging and quantification
Stained tissue was imaged using a Mirax slide scanner. IgG, tau (H-150), Hsp27, and GFAP were quantified in the cortex and hippocampus by segmentation of positive areas using NearCYTE software. As previously reported, this software allows for the segmentation of positive staining based on hue, saturation, and color intensity compared to that of the background in very specific regions of the tissue [33,34]. Consistent color settings were used to analyze each piece of tissue, which was selected for regions of interest based on a mouse brain atlas, across each stain. CD3+ and CD4+ T cells along with H&E positive red blood cells were manually counted by a blinded investigator throughout each section.
For Lectin/tau staining images, z-stack images were taken each 1 μm through the tissue using Leica TCS SP2 Confocal Microscope equipped with a 63x/ 1.4-0.60 PLAN APO Oil objective using Argon and Red HeNe lasers and I3 and N2.1 filters respectively. EB and Hsp27/tau stain was imaged with an AxioCamMR3 camera on a Zeiss AxioImage.Z1 using a 10×/0.25 dry Zeiss EC Plan-Neofluar 10×/0.30 M27 objective. Positive signal was excited using an EXFO X-Cite fluorescence illuminator with 43HE: Cy3 filter (excitation 550/emission 605) at a set exposure time of 750 ms for all tissue. Analysis of EB images was performed using ImageJ software (National Institutes of Health). Images were converted to 8-bit and a threshold of 100-255 was applied. Particle analysis was performed on areas between 0 and infinity pixels2 and a circularity of 0.50-1.00, which allowed for the analysis of all positive EB staining.
Image analysis and statistics
Six to eight sections per mouse were averaged together as a single representative value for a brain region. Statistical analysis was performed either using a 1-way or 2-way analysis of variance (ANOVA) (Age and Genotype) or (Age and Treatment) as appropriate. Values compared between genotypes of a single age group were analyzed by t-test. Values were considered significant when p <0.05. Graphs were generated using GraphPad Prism 5.0.
IgG extravasation in aged rTg4510 mice
Extravasation of immunoglobulin and EB in 12-month old rTg4510 mice
Brain tissue was fixed, sectioned, and mounted for brain region specific analysis of EB. EB fluorescence was found to be highest in 12-month old rTg4510 mice, compared to younger rTg4510 mice or age-matched wild-type mice (Figure 2b). Regions with high EB expression corresponded to those with greatest anti-mouse IgG immunoreactivity (Figure 2c), the highest being the hippocampus and the cortex, followed by the entorhinal cortex and hippocampal commissure. This again shows that periventricular regions are most susceptible to BBB dysfunction , and that this is severely exacerbated in the rTg4510 mouse model. Thus, we analyzed the extravasation of EB in the hippocampus and frontal cortex, since these areas showed prominent IgG infiltration. Significant EB fluorescence was observed in the hippocampus (Figure 2d) and frontal cortex (Figure 2e) of 12-month old rTg4510 mice but not in 6-month old rTg4510 mice or any wild-type mice. Similar to IgG, extravasation of EB was greatest in the CA3 region of the hippocampus (Additional file 1: Figure S1), compared to the CA1 and dentate gyrus, however both of these regions still showed significant EB accumulation. 9-month old rTg4510 mice showed high levels of EB fluorescence in both the hippocampus and frontal cortex which were significant by Student t-test, but not ANOVA. Thus rTg4510 mice can develop a major BBB defect, but this is only significant after 9 months of age, well after robust brain atrophy and tau accumulation begins in this model.
Increasing tau accumulation is accompanied by glial activation
Invasion of red blood cells and T cell lymphocytes is evident in aged rTg4510 mice
As BBB defects are often correlated with entry of immune cells into the brain, staining for CD3+ T cells was performed. CD3+ T cells significantly infiltrated the brain of 12-month old rTg4510 mice (Figure 6c), especially near the longitudinal hippocampal blood vessels (internal transverse hippocampal artery and/or vein; Figure 6d) and periventricular to the lateral ventricles (Figure 6e), but were rarely observed in age-matched wild-type mice (Figure 6f). CD4+ T cells were also found to significantly infiltrate the brains of 12-month old rTg4510 (Figure 6g) mice compared to their younger counterparts and to age-matched wild-type mice. The infiltration of these CD4+ T cells were found in similar regions as CD3+ T cells, along the longitudinal hippocampal blood vessels (Figure 6h) and near periventricular regions (Figure 6i and j). Taken together, these data show that BBB disruption in 12-month old rTg4510 mice is sufficient to not only allow blood components into the brain, but also whole blood cells.
Tau suppression by doxycycline restores BBB integrity
Tau suppression slows and possibly reverses BBB dysfunction in aged rTg4510 mice
T cell lymphocyte and RBC infiltration were also reversed by tau suppression. The RBC counts from 12-month old DOX-treated rTg4510 mice was significantly lower than 12-month old untreated rTg4510 mice and were indistinguishable from 9-month old untreated rTg4510 mice (Figure 9e). We also found that CD3+ (Figure 9f) and CD4+ (Figure 9g) T cells were significantly lower in the DOX-treated rTg4510 mice compared to untreated mice. Unlike CD3+ T cells, CD4+ T cells, while reduced, were still significantly higher in 12-month old DOX-treated rTg4510 mice compared to 9-month old rTg4510 mice.
Appearance of perivascular tau in 12-month old rTg4510 mice
Tau-induced neuronal loss and inflammation are apparent much earlier in the rTg4510 model than BBB dysfunction. But while inflammation in particular is a known regulator of BBB stability , gliosis emerges at nearly the same time and place as tau aggregates begin to appear in the rTg4510 model, both of which occur at a much younger age relative to the emergence of BBB pathology. This suggests that there may be a threshold that tau-induced inflammation and/or neurodegeneration must surpass to induce BBB permeability at 9 months in this model. Alternatively, it could be a distinct pathology that arises, such as the accumulation of perivascular tau, or a combination of these factors. Interestingly, BBB damage in this model appeared greatest in areas such as CA3 and the surface of the cortex, adjacent to the areas that have the most robust neuronal loss and gliosis such as CA1 and frontal mid-cortical layers. In fact, BBB damage was highest near the ventricles and the meninges, the same areas that show signs of BBB leakage in normal aging . In this way, the BBB damage in the rTg4510 brain is similar to that in the normal aging brain with regard to location of initial insult; however this pathology is greatly accelerated, suggesting that the pathologies caused by tau accumulation somehow interact with normal aging pathologies to cause this BBB damage. While the precise mechanism contributing to BBB dysfunction in these mice remains unknown, it is clear that the brain is highly resistant to BBB damage in the face of major pathological insults, and only results through a complex pathogenic cascade much later in the rTg4510 brain.
Still, the specific mechanism by which tau causes BBB dysfunction remains unclear. Perhaps tau aggregation works in a way that is similar to vascular Aß, by decreasing glucose transporters  stimulating reactive oxygen species , and increasing inflammatory molecules [59-61]. In fact, tau accumulation is associated with increased inflammation leading to stimulation of TNF-α and MCP-1, and both of these have been implicated in BBB dysfunction [21,62]. Moreover, the tau accumulating along the vasculature in the rTg4510 mice could be extracellular, perhaps suggesting some type of physical damage to the endothelial cells. There is evidence that tau transgenic models do produce extracellular tau [63,64] and recent work suggests that tau can spread in a prion-like manner in these same mouse models [65-67], further suggesting the potential for a pathological role of extracellular tau. Tau has also been shown to accumulate into annular protofibrils, which may be able to puncture membranes , suggesting perhaps another way for tau to damage the BBB. It is also possible that tau is able to damage the BBB from within cells. In human AD brain, it was recently demonstrated that tau is not only found near the vasculature , but tau oligomers specifically co-localized with endothelial cells within the blood vessels, suggesting that tau was either extracellular or within pericytes or endothelial cells . However our data would suggest that this is not the case in the rTg4510 model, since tau did not strongly co-localize with lectin staining. Another possibility is that neuronal tau accumulation triggers astrocytosis, causing these cells to detach from tight junctions. Also, while likely not relevant to this model because there is no pathological evidence of glial tau in the rTg4510 mice, astrocytic tau has been shown to compromise the BBB by damaging endfeet . Still another mechanism is that tau within endothelial cells themselves can become aberrantly phosphorylated, leading to BBB disruption [54,70,71].
Interestingly, vascular tau is also found in AD cases with CAA [72-74], but this has typically been hypothesized to be downstream of Aß-triggered BBB dysfunction, rather than a causal pathology. There is also evidence that mouse models expressing both mutant amyloid precursor protein or Presenilin 1 have some tau present along the vasculature [13,75], but this was speculated to be a consequence of Aß deposition rather than a pathophysiological function of tau. Thus, while the prevailing dogma in AD is that Aß triggers the BBB dysfunction, our findings clearly show that tau alone is capable initiating impaired BBB stability independent of Aß.
Perivascular tau is also present in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), suggesting that AD is not the only tauopathy to show a BBB defect [76,77]. In contrast to PSP and CBD, AD tau tangles contain exon 10 (+) and exon 10 (-) tau species while tangles from PSP and CBD are exclusively exon 10 (+). Both PSP and AD have neuritic plaques, but only AD has neuropil threads. Moreover, tau pathology in the AD brain originates in the entorhinal cortex and hippocampus, eventually spreading throughout the forebrain, but in PSP tau pathology is restricted to the basal ganglia, brainstem, substantia nigra, and subthalamic nucleus [78,79], and in CBD it is restricted to the cerebral cortex . Perhaps most distinct is that tau in PSP and CBD brain accumulates within astrocytes , while AD brain shows no signs of neuroglial tau pathology. Despite these distinct pathologies, like AD, there is clear evidence for BBB damage in PSP that has been associated with decreased P-glycoprotein, a transporter found in endothelial cells within the BBB [15,77]. Unlike AD where the perivascular tau is thought to arise from neurons, perivascular tau in PSP was attributed to tau derived from tangle bearing thorn-shaped glial cells  and perivascular tau in CBD is most closely associated with astrocytic tau . But, despite different origins, perivascular tau accumulates in each of these diseases, providing further support for a role of tau pathology in BBB damage. Thus, the rTg4510 mice likely most accurately model the BBB defect caused by tau in the AD brain since the tau is neuronally derived and the location of the pathology. However, since the accumulation of perivascular tau is common in each disease, it is possible that the rTg4510 mice, which also have perivascular tau accumulation, could define the role of this particular tau pathology in BBB function.
In summary, we show that tau derived from neurons causes a progressive BBB dysfunction that is most closely correlated with the emergence of perivascular tau, rather than the robust neuronal loss and neuroinflammation that occurs much earlier in the pathogenic cascade of the rTg4510 model. Importantly, reducing tau levels recovered the BBB defect, demonstrating its remarkable resiliency, even in the face of dramatic degeneration and inflammation. Thus, the threshold for BBB integrity is extremely high in the mouse brain and as a result BBB damage appears to be the last chip to fall in the neurotoxic sequelae of this model. Furthermore, this BBB defect in the rTg4510 mouse model can now be used to more adequately model the pharmacokinetic profile of promising pre-clinical therapies to treat tauopathies, since BBB dysfunction is found in AD, traumatic brain injury (TBI) and other tauopathies. Since peripheral infiltration of inflammatory components into the brain is thought to contribute to the late stage sequelae in AD and other tauopathies [82-85], our findings suggest that even late stage interventions targeting tau could help maintain BBB integrity and reduce the vascular contributions to cognitive impairment and dementia that occur in these diseases. Overall, this work demonstrates that tau accumulation can damage the BBB to the point that whole peripheral cells can now enter the brain, perhaps initiating a secondary disease cascade involving the peripheral immune system. But this process is late in the disease process and can be stopped if tau levels are reduced.
Cerebral amyloid angiopathy
Glial fibrillary acidic protein
Hematoxylin and eosin
Heat shock protein 27 kDa
Progressive supranuclear palsy
Red blood cell
Traumatic brain injury
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.
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