Insights into Tanycytes, Tau, And The Hidden Brain Blood Bridge
Curator’s Note: Alzheimer’s disease is characterized by harmful protein accumulation in the brain, particularly Tau and amyloid, which disrupts neuronal function. While it’s known that these proteins are normally cleared from the brain, recent research emphasizes the role of tanycytes—specialized cells in the brain’s ependyma—in this process. Tanycytes help transport Tau from the cerebrospinal fluid (CSF) to the blood, specifically via the pituitary portal system. Disruption in tanycytic transport correlates with increased Tau pathology, suggesting that maintaining healthy tanycytes is crucial for effective Tau clearance. This underscores the importance of both protein production and clearance for brain health, particularly in Alzheimer’s patients. This scholarly essay was written by Dr Khalid Rahman, a health scientist, advanced researcher, and holistic health practitioner.
The mainstream health literature describes Alzheimer’s disease as a condition where harmful proteins collect in the brain. Abnormal Tau and amyloid form tangles and plaques, which disrupt how neurons work and eventually lead to cognitive decline. This explanation mostly looks at how much of this “junk” the brain produces, but it rarely addresses the equally important issue of how the brain gets rid of it.
If you want to see how the process works before diving into the details, you can watch a short video that shows how Tau moves from cerebrospinal fluid to blood through tanycytes in the median eminence:
As life expectancy increases, Alzheimer’s and other cognitive disorders are becoming a serious public health issue. In these situations, proteins like amyloid-beta and Tau build up as plaques and tangles, which are closely linked to problems with neurons and cell death. Normally, these proteins are released from cells and then removed, either by being broken down or transported out of the brain.
Sometimes, this clearing system does not work properly. Tau levels can increase in the cerebrospinal fluid, where Tau is found in soluble forms with changes like phosphorylation and truncation. The CSF serves as a step in a multi-stage process, moving Tau from brain tissue into the CSF and then onward, possibly through the glymphatic system, before it finally leaves the CSF.
It is already known that Tau in the CSF can reach the bloodstream, and Tau in the blood is being studied as a possible biomarker. However, the known pathways do not adequately explain how quickly Tau can leave the CSF in experiments. This gap suggests there may be other, faster ways for Tau to be cleared that have not been completely recognized.
Tanycytes, the new player at the border
Recent research highlights a special type of ependymoglial cell called tanycytes as important players in this missing step. Tanycytes are found along the walls and floor of the third ventricle, especially in parts of the hypothalamus that show changes in gene expression with age.
Traditionally, the movement of molecules from the brain to the blood is explained by two main barriers: the blood–brain barrier, made by endothelial cells in brain blood vessels, and the blood–CSF barrier at the choroid plexus and some special brain regions, including the median eminence. The median eminence has many leaky blood vessels that are part of the pituitary portal system, allowing signals to move between the body, brain, and pituitary.
Tanycytes have long, thin extensions that reach from their cell bodies at the ventricular wall down to endfeet that touch these leaky capillaries. Since the capillaries are not tightly sealed, tanycytes help control what passes through by forming tight junctions at the ventricular wall and acting as gatekeepers between the CSF and the pituitary portal system. They do more than just block things; they also actively move signals from the blood into the CSF, helping the endocrine system and the brain communicate.
This raises an important question – do tanycytes also move molecules from the CSF to the blood? This question led researchers to study their role in moving Tau.
Tanycytes as Tau shuttles
To find out, researchers used both cell cultures and live animal models. In primary rat tanycyte cultures, they exposed the cells to a human 2N4R Tau protein tagged with a fluorescent marker called Tau‑565. This preparation had Tau molecules with one to five fluorescent tags, making it easier to track how the cells took up Tau.
Thirty minutes after the experiment began, vesicles containing Tau appeared inside the tanycytes. Researchers detected these vesicles with Tau-565 fluorescence and confirmed their presence using a Tau-5 antibody. In untreated cells, no Tau signal was seen on a Western blot. However, when cells were briefly exposed to human Tau without the fluorescent tag, clear bands appeared. This result showed that the cells absorbed Tau itself, not just the fluorescent marker.
The vesicles had clathrin and EEA1 markers, which shows that Tau entered the cells through clathrin-mediated endocytosis. Live-cell imaging with a membrane dye revealed Tau-filled vesicles moving inside the tanycytes, supporting the idea of active transport and secretion. Proteins such as VAMP1 suggest that Tau may exit the cells by exocytosis.
After primary tanycytes were briefly exposed to Tau-565 and then placed in fresh medium, a human Tau-specific ELISA showed that Tau levels in the medium rose quickly and continued to increase. This result supports the idea that tanycytes take up Tau from the CSF side, move it along their processes, and then release it to start clearance.
The pituitary route from CSF to blood
To go beyond cell cultures, researchers studied Tau transport in normal mice. They injected Tau‑565 into the lateral ventricle of the brain and tracked it in the pituitary and bloodstream using immunohistofluorescence and ELISA.
Tau signal appeared along the luminal surface of the ventricular wall at all examined time points, and ventral tanycytes became positive for Tau early, with Tau‑565 filling their bodies and processes down to the endfeet. This matched the pattern seen in vitro and supported the idea that tanycytes trap Tau from CSF.
An hour after injection, Tau was no longer visible in tanycytic bodies or their extensions, much like the signal faded over time in cell cultures. Light-sheet imaging of brains thirty minutes after injection showed that Tau‑565 had spread through the ventricular system, but not into the brain tissue or choroid plexus. The strongest signal appeared along the median eminence and ventral tanycytes.
A control protein, BSA‑565, stayed in the ventricular space and did not enter tanycytic structures, showing that the fluorescent label was not causing the transport. Since the blood vessels in the median eminence are part of the pituitary portal system, Tau released at the tanycytic endfeet would likely follow this pituitary route.
After mice were injected with Tau-565, their pituitaries showed fluorescence within thirty minutes. ELISA tests found human Tau in pituitary tissue as early as fifteen minutes and up to an hour after injection. In the blood, Tau was detected around thirty minutes after injection and dropped by the second hour. Deep cervical lymph nodes showed a similar rise and fall, following the same timing as the blood rather than appearing earlier.
Overall, these findings suggest that Tau moves from the CSF to the blood mainly through tanycytes and the pituitary portal system, while lymphatic pathways play a slower role. First, tanycytes take up Tau from the CSF, move it through their extensions, and release it into the portal circulation at the median eminence. From there, Tau travels through the portal system to the front part of the pituitary, drains into pituitary veins with the portal blood, and then enters the general circulation.
What happens when the bridge fails
To find out how important tanycytic vesicular transport is, researchers blocked this pathway only in tanycytes. They used iBot mice with a floxed BoNTB transgene, which was activated by AAV12-Dio2-iCre-GFP. This targeted VAMP1 and VAMP2 to stop exocytosis and VAMP3 to disrupt endocytosis. The viral method mainly affected ependymal cells and, thanks to the Dio2 promoter, increased expression in tanycytes.
In these mice, the Tau‑565 signal in tanycytic extensions, endfeet, and the nearby capillaries was much lower, and less Tau was taken up into tanycytic bodies at the ventricular wall. As a result, the movement of Tau from CSF to blood was reduced. Pituitary Tau was about half as much, and serum Tau dropped to about a quarter compared to normal mice thirty minutes after injection.
In a tauopathy model called THY‑Tau22, blocking this transport (THY‑Tau22 iBot) led to more AT8‑positive Tau pathology, especially in the back part of the hippocampus, and higher levels of harmful Tau types like pS199 and pT181 in hippocampal samples. This connection between disrupted tanycyte transport and worse Tau pathology suggests that healthy tanycyte function helps protect the brain.
Human evidence and the bigger picture
In people with Alzheimer’s disease, the plasma-to-CSF ratios of total Tau and pTau181 are lower, which suggests that less Tau is moving from the CSF to the blood. The ratios of other brain proteins, such as neurofilament light chain and GFAP, do not show this decrease. This points to a problem specific to Tau clearance rather than a general issue with the barrier.
Studies of brains after death show that tanycyte extensions are broken up and look like a string of pearls, instead of being smooth and continuous. These changes happen only in tanycytes, not in astrocytes, and they disrupt how tanycytes interact with capillaries, which likely affects Tau clearance and other exchanges at this border. This fragmentation is seen more often near the third ventricle and the inner part of the median eminence, suggesting a link to CSF exposure.
Transcriptomic analyses offer more detail, showing that hypoxia and oxidative stress pathways, metallothionein genes, and cell death-related factors are strongly activated in Alzheimer’s tanycytes. Together with structural beading, stress responses, and changes in vesicle transport, these results suggest that tanycytic dysfunction is common and affects Tau clearance.
Looking at data from cell cultures, animals, and humans, this research builds a clear model of a brain‑to‑blood tanycytic shuttle for Tau that does not work well in Alzheimer’s disease. Any treatment that keeps this shuttle’s structure and transport working, or repairs it if damaged, could help fix the Tau clearance problem and may reduce Tau buildup and its effects.
This means that brain health depends not just on how much Tau is made, but also on how well it is cleared across this hidden bridge between CSF and blood.
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Dr. Khalid Rahman
Health Scientist | Scholarly Communicator | Licensed Integrative Medicine Practitioner | PhD (Clinical Research) | MSc (Bioinformatics) | MSc (Clinical Research & Regulatory Affairs) | Post Graduate Diploma in Computer Application | Bachelor of Unani Medicine & Surgery
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