Barshop Institute for Longevity and Aging Studies, University of Texas Health, San Antonio, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health, San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, San Antonio, TX, USA.
Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, San Antonio, TX, USA; Greehey Children's Cancer Institute, University of Texas Health, San Antonio, San Antonio, TX, USA.
Cell Rep. 2020 Jul 14;32(2):107900. doi: 10.1016/j.celrep.2020.107900.
Synaptic activity-induced calcium (Ca) 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 Ca 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 Ca. We find that pathogenic tau depletes nuclear Ca 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 Ca and suppresses tau-induced neurotoxicity. Our studies identify nuclear Ca depletion as a mechanism contributing to tau-induced neurotoxicity, adding an important dimension to the calcium hypothesis of Alzheimer's disease.
突触活动诱导的钙（Ca）内流，以及随后向核内的传播，是突触与核通讯的主要方式之一，可调节与活动依赖性存活和记忆形成相关的重要转录程序。核内 Ca 通过调节环腺苷酸（cAMP）反应元件结合蛋白（CREB）来重塑转录组。在这里，我们利用阿尔茨海默病的 tau 病果蝇模型和源自阿尔茨海默病患者的诱导多能干细胞（iPSC）衍生神经元，研究致病性 tau（阿尔茨海默病和相关 tau 病的病理标志）对核内 Ca 的影响。我们发现致病性 tau 会耗尽核内 Ca 和 CREB，从而导致神经元死亡，在 tau 转基因果蝇中差异表达的基因中，CREB 调节的基因过度表达，而大钾（BK）通道的激活可增加核内 Ca 并抑制 tau 诱导的神经毒性。我们的研究确定了核内 Ca 耗竭是导致 tau 诱导的神经毒性的一种机制，为阿尔茨海默病的钙假说增添了一个重要维度。
