Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium

Synaptic activity-induced calcium (Ca²⁺) influx and subsequent propagation into the nucleus is a major way in which synapses communicate with the nucleus to regulate transcriptional programs important for activity-dependent survival and memory formation. Nuclear Ca²⁺ shapes the transcriptome by regulating cyclic AMP (cAMP) response element-binding protein (CREB). Here, we utilize a Drosophila model of tauopathy and induced pluripotent stem cell (iPSC)-derived neurons from humans with Alzheimer's disease to study the effects of pathogenic tau, a pathological hallmark of Alzheimer's disease and related tauopathies, on nuclear Ca²⁺. We find that pathogenic tau depletes nuclear Ca²⁺ and CREB to drive neuronal death, that CREB-regulated genes are over-represented among differentially expressed genes in tau transgenic Drosophila, and that activation of big potassium (BK) channels elevates nuclear Ca²⁺ and suppresses tau-induced neurotoxicity. Our studies identify nuclear Ca²⁺ depletion as a mechanism contributing to tau-induced neurotoxicity, adding an important dimension to the calcium hypothesis of Alzheimer's disease.

Keywords: Alzheimer’s disease; BK channels; CREB; Drosophila; calcium; iPSC-derived neurons; neurodegeneration; nucleus; tau; tauopathy.