Secretion of Pathological Tau Via an Unconventional, Non-vesicular Mechanism

Abstract

Cerebral accumulation of Tau protein aggregates, in the form of neurofibrillary tangles, is a pathological hallmark of numerous neurodegenerative disorders including Alzheimer's disease. In these tauopathies, Tau forms inclusions that spread throughout the brain via a cell-to-cell transmission process that includes cellular secretion and uptake of pathological Tau, followed by templated misfolding of normal Tau in recipient cells. The mechanism of Tau secretion remains poorly understood. Here we show that Tau is secreted independently of membrane trafficking or ATP, and that Tau is clustered in sub-plasma membrane microdomains. Tau secretion is decreased when levels of cholesterol or sphingomyelin on the plasma membrane are lowered, or by increasing the levels of omega-3 fatty acid docosahexanoic acid, indicating that plasma membrane lipids and biophysical properties play an important role in Tau secretion. Cell surface heparan sulphate proteoglycans support Tau secretion, possibly by facilitating its release after membrane penetration. Several Tau aggregation inhibitors reduce Tau secretion, with epigallocatechin-3-gallate showing the most potent effects. Together, these results suggest that Tau is released by an unconventional secretory mechanism that involves hyperphosphorylation and oligomerization, and that membrane interaction may help Tau to acquire properties that allow its escape from cells directly through the plasma membrane.