Tanycytic degradation in Alzheimer Disease disrupts Tau clearance, contributing to pathogenesis

Alzheimer’s disease (AD) is characterized by the accumulation of pathological Tau protein in the brain and cerebrospinal fluid (CSF), instead of its timely efflux into the blood. However, clearance mechanisms for brain Tau are poorly understood. We show here, using animal and cellular models as well as patient tissues, that tanycytes of the hypothalamic median eminence, which bridge the blood and CSF and act as shuttles between the two compartments, carry out this clearance, and their dysfunction is associated with AD pathogenesis. In mice, tanycytes take up Tau from the CSF and release it into pituitary portal blood vessels, whence it eventually enters the systemic circulation. Specifically blocking tanycytic vesicular transport blunts CSF-to-blood Tau transfer and potentiates Tau pathology in a mouse model. In AD patients from two cohorts, plasma-to-CSF ratios of total Tau and Tau p181, proxies for CSF-to-blood Tau clearance, are decreased, supporting dysfunctional Tau efflux. Tanycytic morphology is altered in the postmortem brains of both patients with AD and those with frontotemporal dementia; however, tanycytic processes display dramatic fragmentation only in AD, in keeping with reduced Tau clearance in the former. Single-nucleus RNA sequencing reveals significant alterations of gene expression in tanycytes from AD patients, supporting the notion of AD-driven pathological changes in tanycytes and shedding light on their putative mechanisms and consequences. This unprecedented implication of tanycytic fragmentation and dysfunction in the pathophysiology of a human disease and the evidence for a brain-to-blood tanycytic shuttle have far-reaching implications for both AD and other disorders.