Tanycytic degeneration impairs tau clearance and contributes to Alzheimer’s disease pathology

Alzheimer's disease (AD) is characterized by pathological Tau protein accumulation in the brain and cerebrospinal fluid (CSF), instead of timely efflux into the blood. However, the underlying mechanisms are unclear. We show, using animal and cellular models and patient tissues, that tanycytes of the hypothalamic median eminence, which bridge the blood and CSF, are involved in Tau transport and AD pathogenesis. In mice, tanycytes take up CSF-borne Tau and release it into pituitary portal capillaries, whence it enters the systemic circulation. Blocking tanycytic vesicular transport blunts CSF-to-blood Tau efflux and potentiates Tau pathology. In AD patients, plasma-to-CSF ratios of total and p181 Tau are decreased. Tanycytes from postmortem AD patient brains display dramatically fragmented processes and significant transcriptomic alterations by single-nucleus RNA sequencing, notably in vesicular-transport-related genes, explaining this clearance deficit. The involvement of tanycytic dysfunction in human pathophysiology and evidence for a brain-to-blood tanycytic shuttle has far-reaching implications.