Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium

Rebekah Mahoney, Elizabeth Ochoa Thomas, Paulino Ramirez, Henry E. Miller, Adrian Beckmann, Gabrielle Zuniga, Radek Dobrowolski, Bess Frost

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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.

Original languageEnglish (US)
Article number107900
JournalCell Reports
Issue number2
StatePublished - Jul 14 2020


  • Alzheimer's disease
  • BK channels
  • CREB
  • Drosophila
  • calcium
  • iPSC-derived neurons
  • neurodegeneration
  • nucleus
  • tau
  • tauopathy

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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