FAM84B facilitates tau propagation via RYR3-mediated exocytosis in response to neuroinflammation

Abstract

The increasing prevalence of dementia underscores the pressing need for effective therapeutic interventions. Despite extensive research into A{beta}, the limited efficacy of existing treatment modalities necessitates a paradigm shift toward tau pathology including tau propagation to slow dementia progression. Here, we identified a novel protein, FAM84B (also known as LRATD2), involved in tau propagation. Elevated FAM84B levels were detected in the postmortem cortex, cerebrospinal fluid, and induced pluripotent stem cell-derived cortical neurons of patients with tauopathy. FAM84B facilitates tau secretion through exosome assembly and RYR3-mediated exocytosis, followed by exosomal uptake into neighboring cells via clathrin-mediated endocytosis, thereby driving tau propagation. We confirmed that neuroinflammation induced by heightened STAT3 activity and cytokine treatment upregulated FAM84B expression, stimulating tau propagation, as evidenced by reduced propagation upon RYR3 inhibition. These findings provide invaluable insights into potential avenues for targeting tau propagation to ameliorate disease progression in tauopathies.