Amyloid-beta levels are significantly reduced and spatial memory defects are rescued in a novel neuroserpin-deficient Alzheimer's disease transgenic mouse model
Amyloid-beta levels are significantly reduced and spatial memory defects are rescued in a novel neuroserpin-deficient Alzheimer's disease transgenic mouse model
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DOI：
10.1111/j.1471-4159.2011.07359.x
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发表时间：
2011-09-01
影响因子：
4.7
通讯作者：
Seeds, Nicholas W.
中科院分区：
文献类型：
--
作者：
Fabbro, Shay;Schaller, Kristin;Seeds, Nicholas W.
β 淀粉样蛋白 (Aβ) 斑块是阿尔茨海默病的一个标志。包括纤溶酶在内的几种蛋白酶被认为可以促进 Aβ 从大脑中的蛋白水解裂解和清除。在阿尔茨海默病患者的大脑中，纤溶酶和组织纤溶酶原激活剂的活性均降低，而组织纤溶酶原激活剂抑制剂神经丝氨酸蛋白酶抑制剂则上调。在这里，我们在小鼠模型中探讨了组织纤溶酶原激活剂和神经丝氨酸蛋白酶抑制剂与 Aβ 水平的关系。与野生型小鼠相比，注射到组织纤溶酶原激活物敲除小鼠额叶皮质中的β(1-42)肽消失缓慢，而神经丝氨酸蛋白酶抑制剂敲除小鼠则显示出Aβ(1-42)的快速清除。通过在人淀粉样前体蛋白-J20转基因小鼠中敲除神经丝氨酸蛋白酶抑制剂，进一步研究了神经丝氨酸蛋白酶抑制剂和组织纤溶酶原激活剂与Aβ斑块形成的关系。与J20转基因小鼠相比，缺乏神经丝氨酸蛋白酶抑制剂的J20转基因小鼠的Aβ肽显着减少，斑块更少且更小，并且与斑块相关的组织纤溶酶原激活剂活性更高。此外，神经丝氨酸蛋白酶抑制剂缺陷的J20转基因小鼠在莫里斯水迷宫中的表现接近正常，这与J20转基因小鼠中观察到的空间记忆缺陷形成鲜明对比。这些结果支持这样的概念：神经丝氨酸蛋白酶抑制剂对组织纤溶酶原激活剂的抑制在脑淀粉样斑块的积累和认知能力丧失中发挥重要作用。
Amyloid-beta (A beta) plaques are a hallmark of Alzheimer's disease. Several proteases including plasmin are thought to promote proteolytic cleavage and clearance of A beta from brain. The activity of both plasmin and tissue plasminogen activator are reduced in Alzheimer's disease brain, while the tissue plasminogen activator inhibitor neuroserpin is up-regulated. Here, the relationship of tissue plasminogen activator and neuroserpin to A beta levels is explored in mouse models. A beta(1-42) peptide injected into the frontal cortex of tissue plasminogen activator knockout mice is slow to disappear compared to wildtype mice, whereas neuroserpin knockout mice show a rapid clearance of A beta(1-42). The relationship of neuroserpin and tissue plasminogen activator to A beta plaque formation was studied further by knocking-out neuroserpin in the human amyloid precursor protein-J20 transgenic mouse. Compared to the J20-transgenic mouse, the neuroserpin-deficient J20-transgenic mice have a dramatic reduction of A beta peptides, fewer and smaller plaques, and more active tissue plasminogen activator associated with plaques. Furthermore, neuroserpin-deficient J20-transgenic mice have near normal performances in the Morris water maze, in contrast to the spatial memory defects seen in J20-transgenic mice. These results support the concept that neuroserpin inhibition of tissue plasminogen activator plays an important role both in the accumulation of brain amyloid plaques and loss of cognitive abilities.