Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant.
Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant.
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DOI：
10.1016/j.neurobiolaging.2015.09.007
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发表时间：
2015-12
影响因子：
4.2
通讯作者：
Ziff EB
中科院分区：
文献类型：
--
作者：
Kim S;Violette CJ;Ziff EB
阿尔茨海默病（AD）是最常见的神经退行性疾病之一，其特征是记忆丧失和认知障碍。虽然大多数 AD 病例是散发性的，但有些是由早发家族性 AD (FAD) 基因突变引起的。一个 FAD 基因编码早老素 1 (PS1)，而蛋氨酸 146 中的 PS1 突变会损害稳态突触可塑性 (HSP)。我们之前已经证明 Ca2+ 和钙调神经磷酸酶活性是 HSP 的关键调节因子。在这里，我们证实突变型 PS1 神经元中 ER 介导的 Ca2+ 信号增加。我们进一步表明，突变体中钙调磷酸酶活性异常升高，并且抑制钙调磷酸酶活性的增加可以稳定 GluA1 磷酸化，促进 Ca2+ 通透性 AMPA 受体的突触运输，从而有助于恢复突变体中发现的受损 HSP。由于 HSP 被认为在学习和记忆形成过程中发挥作用，因此钙调神经磷酸酶活性增加引起的 HSP 损伤可导致 FAD 认知能力下降。因此，减少 AD 大脑中异常增加的钙调神经磷酸酶活性可能有利于改善 AD 相关的认知能力下降。
Alzheimer disease (AD) is one of the most common neurodegenerative diseases characterized by memory loss and cognitive impairment. While the majority of AD cases are sporadic, some are caused by mutations in early-onset familial AD (FAD) genes. One FAD gene encodes presenilin 1 (PS1), and a PS1 mutation in methionine 146 impairs homeostatic synaptic plasticity (HSP). We have previously shown that Ca2+ and calcineurin activity are critical regulators of HSP. Here, we confirm that ER-mediated Ca2+ signals are increased in mutant PS1 neurons. We further show that calcineurin activity is abnormally elevated in the mutant, and that inhibition of increased calcineurin activity stabilizes GluA1 phosphorylation, promoting synaptic trafficking of Ca2+-permeable AMPA receptors, contributing to the recovery of impaired HSP found in the mutant. Because HSP is suggested to have roles during learning and memory formation, increased calcineurin activity-induced impairment of HSP can cause cognitive decline in FAD. Thus, reducing abnormally increased calcineurin activity in AD brain may be beneficial for improving AD-related cognitive decline.