Sauvé F, Ternier G, Dewisme J, Lebouvier T, Dupré E, Danis C, Rasika S, Kim YB, Ciofi P, Giacobini P, Buée L, Landrieu I, Pasquier F, Maurage CA, Nogueiras R, Schwaninger M, Prevot V. Tanycytes are degraded in Alzheimer’s Disease, disrupting the brain-to-blood efflux of Tau. medRxiv, May 7, 2022 medRxiv
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University College London
UCL
Tanycytes are an unusual class of cell in the brain, serving as a communication site between the cerebrospinal fluid (CSF) and the pituitary portal circulation (Prevot et al., 2018). These ependymoglial cells line the third ventricle and stretch long processes to the fenestrated capillaries of the median eminence. Their most explored roles are in the shuttling of blood-borne signals into the CSF (Mullier et al., 2010), and in regulating metabolic networks and hormone secretion (Rodríguez et al., 2019).
This preprint, however, takes a different approach to previous studies and looks at other potential roles that tanycytes might play in the context of neurodegenerative diseases, specifically focussing on tau. Florent Sauvé and colleagues demonstrate, both in vitro and in vivo, that tanycytes act as tau transporters. They note tanycyte endocytosis and subsequent exocytosis of tau in culture, and the translocation of tau in vivo from ventricular CSF toward the pituitary, to which the portal capillaries of the median eminence lead. Interestingly, the authors show the curious specificity of these cells for tau over similar-molecular-weight proteins (e.g., bovine serum albumin). Furthermore, using an animal model, the study shows that prevention of endocytosis in tanycytes leads to a reduction of tau in tanycytic processes and the underlying capillary bed.
This is the first evidence showing that these specialized cells are not only capable of endocytosing molecules that are not necessarily produced by them, but also that tanycytic cells have bi-directional secretory activity. In addition, in their study of human brain tissue, the authors present compelling evidence suggestive of profound changes in the structure of tanycytes in Alzheimer’s disease, with remarkable fragmentation and structural changes in the cytoskeleton of these cells. Looking at other neurodegenerative diseases, too (both TDP-43 and tau-type frontotemporal dementia cases), tanycyte morphology was again observed to be different from controls.
Why are these findings relevant for the tauopathy field? It has long been known that tau is transported out of the brain to the peripheral circulation, but the precise mechanisms of how tau crosses the blood-brain barrier to reach the circulating blood pool are only recently coming to light.
One popular area of investigation in this field is in the glymphatic clearance pathway, shown previously to be involved in tau brain clearance (Iliff et al., 2014; Harrison et al., 2020), and numerous intracranial structures/systems have been proposed to be involved, e.g., the arachnoid villi, the choroid plexus and the meningeal lymphatic vessels/system.
Adding tanycyte-facilitated clearance to this list, as this preprint proposes, adds a level of complexity to our understanding of the interplay of these pathways. For example, how much each of these pathways proportionally contributes to the clearance of tau protein from the brain remains up for debate. While the study does not address the relative contribution of this novel pathway in the total clearance of tau from the brain, it reveals a major role of tanycyte tau efflux: Impairment leads to a 3.5-fold reduction of tau in the plasma. Further, the degradation of this cell type that the authors see in neurodegenerative diseases provides an exciting additional avenue of research into the interaction of the brain and periphery and its implication in disease, not only in the context of tauopathies but potentially in other amyloidoses.
References:
Harrison IF, Ismail O, Machhada A, Colgan N, Ohene Y, Nahavandi P, Ahmed Z, Fisher A, Meftah S, Murray TK, Ottersen OP, Nagelhus EA, O'Neill MJ, Wells JA, Lythgoe MF. Impaired glymphatic function and clearance of tau in an Alzheimer's disease model. Brain. 2020 Aug 1;143(8):2576-2593. PubMed.
Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, Singh I, Deane R, Nedergaard M. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci. 2014 Dec 3;34(49):16180-93. PubMed.
Mullier A, Bouret SG, Prevot V, Dehouck B. Differential distribution of tight junction proteins suggests a role for tanycytes in blood-hypothalamus barrier regulation in the adult mouse brain. J Comp Neurol. 2010 Apr 1;518(7):943-62. PubMed.
Prevot V, Dehouck B, Sharif A, Ciofi P, Giacobini P, Clasadonte J. The Versatile Tanycyte: A Hypothalamic Integrator of Reproduction and Energy Metabolism. Endocr Rev. 2018 Jun 1;39(3):333-368. PubMed.
Rodríguez E, Guerra M, Peruzzo B, Blázquez JL. Tanycytes: A rich morphological history to underpin future molecular and physiological investigations. J Neuroendocrinol. 2019 Mar;31(3):e12690. Epub 2019 Mar 10 PubMed.
The University of Tokyo
University of Tokyo
This interesting paper supports the notion that there may exist multiple pathways involved in the elimination of tau from brain parenchyma as well as from CSF. It is quite interesting that ablation of a small population of a specific cell type, i.e., tanycytes, strongly impacted the transport of tau from CSF to blood.
It would be nice if the authors could also investigate whether disruption of this new clearance pathway altered the levels of endogenous tau in CSF and blood in the Dio2-Cre/BoNT mice, since we have recently seen a marked increase in CSF tau in our tau transgenic (PS19) mice lacking AQP-4. In these mice, failure of the glymphatic system caused retardation in clearance of soluble tau from the brain parenchyma, and increased levels of tau in the CSF (Ishida et al., 2022).
Another interesting technical question would be whether the route of administration of labeled tau into the CSF may influence which clearance pathway predominates. Sauvé et al. chose intraventricular injection, whereas direct intrathecal injection, e.g., into the cisterna magna, is another frequently used method to trace the clearance of substances in CSF.
In any case, investigations into the mechanisms of clearance of soluble and insoluble forms of tau from brain/CSF to the systemic circulation will facilitate our understanding of the tau-induced neurodegeneration in AD and other neurodegenerative disorders.
References:
Ishida K, Yamada K, Nishiyama R, Hashimoto T, Nishida I, Abe Y, Yasui M, Iwatsubo T. Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. J Exp Med. 2022 Mar 7;219(3) Epub 2022 Feb 25 PubMed.
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