Abstract / Summary
The increasing prevalence of dementia underscores the pressing need for effective therapeutic interventions. Despite extensive research into amyloid-β, the modest clinical benefits achieved to date have prompted growing interest in tau pathology and intercellular tau transfer as potential therapeutic targets. However, molecular regulators linking neuroinflammation to tau transfer remain poorly understood. Here, we identified family with sequence similarity 84 member B (FAM84B; also known as LRATD2) as a novel regulator of intercellular tau transfer. Elevated FAM84B levels were detected in postmortem cortical tissues from patients with tauopathies and induced pluripotent stem cell-derived cortical neurons from patients with AD. Increased FAM84B expression enhanced tau secretion in association with ryanodine receptor 3-linked calcium signaling, and the released tau was subsequently taken up by neighboring cells in part through clathrin-associated endocytosis, thereby promoting cell-to-cell tau transfer. We further found that neuroinflammatory signaling involving signal transducer and activator of transcription 3 activation was associated with increased tau transfer. Proinflammatory cytokine treatment upregulated FAM84B expression, whereas pharmacological inhibition of ryanodine receptor signaling with dantrolene, suppressed the associated increase in tau transfer. FAM84B may participate in a neuroinflammation-associated process that redistributes tau toward extracellular release and intercellular transfer. These findings identify a potential mechanistic link between neuroinflammation and tau transfer and highlight FAM84B-associated pathways as potential mechanistic targets for further investigation in tauopathies.