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

Abstract

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.