Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium

Cell Rep. 2020 Jul 14;32(2):107900. doi: 10.1016/j.celrep.2020.107900.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Animals, Genetically Modified
  • Brain / metabolism
  • Calcium / metabolism*
  • Cell Nucleus / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Induced Pluripotent Stem Cells / metabolism
  • Membrane Potentials
  • Neurons / metabolism
  • Neurotoxins / toxicity
  • tau Proteins / metabolism*


  • Cyclic AMP Response Element-Binding Protein
  • Neurotoxins
  • tau Proteins
  • Calcium