FRMD4A–cytohesin signaling modulates the cellular release of tau

One of the defining pathological features of Alzheimer's disease (AD) is the intraneuronal accumulation of Tau protein. Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of AD patients. Tau pathology may spread from cell to cell via a mechanism involving secretion and uptake. We developed an assay to follow cellular release and uptake of Tau dimers. RNAi knockdown of ten common late-onset AD risk genes in HEK293T cells expressing the Tau reporters suggested that FRMD4A is functionally linked to Tau secretion. FRMD4A RNAi reduced and overexpression increased Tau secretion. Activity of cytohesins, interactors of FRMD4A and guanine-nucleotide exchange factors of Arf6, was necessary for FRMD4A-induced Tau secretion. Increased Arf6 and cell polarity signaling via Par6 and aPKCζ stimulated Tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous Tau. These results suggest that FRMD4A, a genetic risk factor for late-onset AD, regulates Tau secretion by activating cytohesin-Arf6 signaling. We conclude that genetic risk factors of AD may modulate disease progression by altering Tau secretion.