Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium Mediated by BK Channels

Abstract

Synaptic activity-induced calcium ion (Ca²⁺) influx and subsequent propagation of Ca²⁺ into the nucleus is a major way in which synapses communicate with the nucleus to regulate transcriptional programs that maintain activity-dependent survival and mediate memory formation. Nuclear Ca²⁺ shapes the transcriptome by regulating cAMP response element-binding protein (CREB)-dependent transcription. Here we utilize Drosophila and induced pluripotent stem cell (iPSC)-derived neurons from humans with Alzheimer’s disease to study the effects of pathogenic tau, a 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. Mechanistically, we find that big potassium (BK) channels regulate depletion of nuclear Ca²⁺ in tauopathy, and that genetic and pharmacologic manipulation of nuclear Ca²⁺ and BK channels modifies tau neurotoxicity. Our studies identify the BK channel/nuclear Ca²⁺/CREB axis as a previously unknown mechanism contributing to tau-induced neurotoxicity, adding a new dimension to the Calcium Hypothesis of Alzheimer’s Disease.

Keywords: Alzheimer's disease, Tau, neurodegeneration, nucleus, calcium, CREB, BK channels, Drosophila, iPSC