Neprilysin-sensitive synapse-associated amyloid-β peptide oligomers impair neuronal plasticity and cognitive function
Neprilysin-sensitive synapse-associated amyloid-β peptide oligomers impair neuronal plasticity and cognitive function
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DOI：
10.1074/jbc.m601372200
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发表时间：
2006-06-30
影响因子：
4.8
通讯作者：
Iwata, Nobuhisa
中科院分区：
文献类型：
--
作者：
Huang, Shu-Ming;Mouri, Akihiro;Iwata, Nobuhisa
淀粉样β肽（Aβ）合成代谢和分解代谢活动之间代谢平衡的微妙但慢性的改变被认为会导致Aβ积累，从而导致阿尔茨海默病长达十年的病理级联反应。然而，目前尚不清楚大脑中 Aβ 分解代谢活性的降低是否会导致体内神经元功能障碍。在本研究中，为了阐明脑啡肽酶活性降低与突触和认知功能受损之间可能存在的联系，我们将淀粉样前体蛋白（APP）转基因小鼠（APP23）与脑啡肽酶缺陷小鼠杂交，并通过生化和免疫电子显微镜分析了大脑中Aβ的积累。我们还使用体内记录技术检查海马突触可塑性，并使用一系列学习和记忆行为测试检查认知功能，包括 Y 迷宫、新奇物体识别、莫里斯水迷宫和 13-16 周龄的情境恐惧条件反射测试。我们提出的直接实验证据表明，脑啡肽酶（主要的 A β 降解酶）活性降低会升高突触处 A β 寡聚形式，并导致海马突触可塑性和认知功能受损，然后出现淀粉样斑块负荷。因此，中性溶酶活性降低似乎是导致阿尔茨海默病记忆相关症状的至少部分原因。这支持了这样的观点：通过上调脑啡肽酶活性来减少大脑中 Aβ 寡聚体的策略将有助于缓解这些症状。
A subtle but chronic alteration in metabolic balance between amyloid-beta peptide(A beta) anabolic and catabolic activities is thought to cause A beta accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of A beta in the brain causes neuronal dysfunction in vivo. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred amyloid precursor protein (APP) transgenic mice (APP23) with neprilysin-deficient mice and biochemically and immunoelectron-microscopically analyzed A beta accumulation in the brain. We also examined hippocampal synaptic plasticity using an in vivo recording technique and cognitive function using a battery of learning and memory behavior tests, including Y-maze, novel-object recognition, Morris water maze, and contextual fear conditioning tests at the age of 13-16 weeks. We present direct experimental evidence that reduced activity of neprilysin, the major A beta-degrading enzyme, in the brain elevates oligomeric forms of A beta at the synapses and leads to impaired hippocampal synaptic plasticity and cognitive function before the appearance of amyloid plaque load. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of Alzheimer disease. This supports the idea that a strategy to reduce A beta oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms.