Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Key Laboratory of Psychotic Disorders (No.13dz2260500), Shanghai Mental Health Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
Cell Rep. 2022 Mar 29;38(13):110594. doi: 10.1016/j.celrep.2022.110594.
Evidence suggests that impaired synaptic and firing homeostasis represents a driving force of early Alzheimer's disease (AD) progression. Here, we examine synaptic and sleep homeostasis in a Drosophila model by overexpressing human amyloid precursor protein (APP), whose duplication and mutations cause familial early-onset AD. We find that APP overexpression induces synaptic hyperexcitability. RNA-seq data indicate exaggerated expression of Ca-related signaling genes in APP mutants, including genes encoding Dmca1D, calcineurin (CaN) complex, and IPR. We further demonstrate that increased CaN activity triggers transcriptional activation of Itpr (IPR) through activating nuclear factor of activated T cells (NFAT). Strikingly, APP overexpression causes defects in synaptic downscaling and sleep deprivation-induced sleep rebound, and both defects could be restored by inhibiting IPR. Our findings uncover IPR as a shared signaling molecule in synaptic downscaling and sleep homeostasis, and its dysregulation may lead to synaptic hyperexcitability and AD progression at early stage.
有证据表明，突触和放电稳态的损伤代表了早期阿尔茨海默病（AD）进展的驱动力。在这里，我们通过过表达人类淀粉样前体蛋白（APP）来检查果蝇模型中的突触和睡眠稳态，APP 的复制和突变会导致家族性早发性 AD。我们发现 APP 过表达会引起突触过度兴奋。RNA-seq 数据表明，APP 突变体中 Ca 相关信号基因的表达明显增加，包括编码 Dmca1D、钙调神经磷酸酶（CaN）复合物和 IPR 的基因。我们进一步证明，增加的 CaN 活性通过激活活化 T 细胞核因子（NFAT）触发 IPR（IPR）的转录激活。引人注目的是，APP 过表达导致突触缩小和睡眠剥夺诱导的睡眠反弹缺陷，而通过抑制 IPR 可以恢复这两种缺陷。我们的研究结果揭示了 IPR 作为突触缩小和睡眠稳态的共同信号分子，其失调可能导致早期突触过度兴奋和 AD 进展。
