Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice
Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice
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DOI：
10.1016/j.nlm.2007.03.010
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发表时间：
2007-09-01
影响因子：
2.7
通讯作者：
Taglialatela, Giulio
中科院分区：
文献类型：
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作者：
Dineley, Kelly T.;Hogan, Dale;Taglialatela, Giulio
错误折叠的淀粉样蛋白β肽（A β）是阿尔茨海默病（AD）的病理标志，AD是一种以认知缺陷和神经元损失为特征的神经退行性疾病。A β过度产生的转基因小鼠模型表明，A β诱导的认知缺陷在没有明显神经元死亡的情况下发生，这表明虽然广泛的神经元死亡可能与人类疾病的后期阶段有关，但微妙的生理变化可能是初始认知缺陷的基础。因此，识别在神经元丧失之前发生的A β诱导的认知障碍中涉及的信号传导元件可能揭示新的潜在药理学靶点。在这里，我们报告说，钙调磷酸酶（一种参与磷酸化依赖性激酶活性的关键蛋白磷酸酶，对突触可塑性和记忆功能至关重要）的酶活性在A β过度产生的Tg 2576动物模型的中枢神经系统中上调。此外，用钙调磷酸酶抑制剂FK 506（10 mg/kg i. p.）改善记忆功能。这些结果表明，钙调神经磷酸酶可能介导过量A β的一些认知效应，因此应进一步探索钙调神经磷酸酶的抑制作为逆转AD认知障碍的潜在治疗。(C)2007年爱思唯尔公司All rights reserved.
Misfolded amyloid beta peptide (A beta) is a pathological hallmark of Alzheimer's disease (AD), a neurodegenerative illness characterized by cognitive deficits and neuronal loss. Transgenic mouse models of A beta over-production indicate that A beta-induced cognitive deficits occur in the absence of overt neuronal death, suggesting that while extensive neuronal death may be associated with later stages of the human disease, subtle physiological changes may underlie initial cognitive deficits. Therefore, identifying signaling elements involved in those A beta-induced cognitive impairments that occur prior to loss of neurons may reveal new potential pharmacological targets. Here, we report that the enzymatic activity of calcineurin, a key protein phosphatase involved in phosphorylation-dependent kinase activity crucial for synaptic plasticity and memory function, is upregulated in the CNS of the Tg2576 animal model for A beta over-production. Furthermore, acute treatment of Tg2576 mice with the calcineurin inhibitor FK506 (10 mg/kg i.p.) improves memory function. These results indicate that calcineurin may mediate some of the cognitive effects of excess A beta such that inhibition of calcineurin shall be further explored as a potential treatment to reverse cognitive impairments in AD. (C) 2007 Elsevier Inc. All rights reserved.