Tanycytes are degraded in Alzheimer’s Disease, disrupting the brain-to-blood efflux of Tau

The accumulation of pathological Tau in the brain and cerebrospinal fluid (CSF) and its eventual increase in the blood are hallmarks of Alzheimer’s disease (AD). However, the mechanisms of Tau clearance from the brain to the periphery are not clear. We show here, using animal and cellular models as well as patient blood samples and post mortem brains, that hypothalamic tanycytes, whose cell bodies line the ventricular wall and send long processes to the underlying pituitary portal capillary bed, take up and transport Tau from the CSF and release it into these capillaries, whence it travels to the pituitary and eventually the systemic circulation. Specifically blocking tanycytic vesicular transport leads to an accumulation of exogenous fluorescent Tau in the CSF of mice. In AD and frontotemporal dementia, tanycytic morphology is altered, with a dramatic fragmentation of the secondary cytoskeleton in the former but not the latter, accounting for reduced CSF Tau clearance in AD. Both the implication of tanycytic degradation in the pathophysiology of a human disease and the evidence for the existence of a brain-to-blood tanycytic shuttle are unprecedented, and raise important questions regarding the role of tanycytes in physiological clearance mechanisms and the development of neurodegenerative disorders. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the European Research Council (ERC) Synergy Grant-2019-WATCH No 810331, DistAlz (no. ANR-11-LABEX-0009), EGID (no. ANR-10-LABEX-0046), I-SITE ULNE (no. ANR-16-IDEX-0004) and National Institutes of Health (R01DK123002). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Tissues were obtained in accordance with French laws (Good Practice Concerning the Conservation, Transformation and Transportation of Human Tissue to be Used Therapeutically, published on December 29, 1998). Permission to use human tissues was obtained from the French Agency for Biomedical Research (Agence de la Biomedecine, Saint-Denis la Plaine, France, protocol no. PFS16-002) and the Lille Neurobiobank. Ethics committee, CPP SUD-EST II, gave ethical approval for this work (BIOWATCH, 2021-A00879-32) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors Data collection and sharing for this project was funded by the Alzheimer Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer Association; Alzheimer Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ([www.fnih.org][1]). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. [1]: http://www.fnih.org