Amyloid activates GSK-3β to aggravate neuronal tauopathy in bigenic mice
Amyloid activates GSK-3β to aggravate neuronal tauopathy in bigenic mice
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DOI：
10.2353/ajpath.2008.070904
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发表时间：
2008-03-01
影响因子：
6
通讯作者：
Van Leuven, Fred
中科院分区：
文献类型：
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作者：
Terwel, Dick;Muyllaert, David;Van Leuven, Fred
通过鉴定GSK-3同工酶作为淀粉样蛋白到tau病理信号通路的主要环节，实验支持了淀粉样蛋白病理先于并诱导阿尔茨海默病tau病理的假设。本研究比较了两种新的双基因小鼠模型：具有淀粉样蛋白和tau蛋白联合病理的APP-V717I x tau - p301l小鼠和仅具有tau病的GSK-3 β x tau - p301l小鼠。在这些菌株之间观察到广泛和显著的相似之处，包括：1)海马和皮层中高度纤维缠结的脑损伤加重；2)脑干脑损伤减轻与延长生存期相关；3)在淀粉样蛋白沉积或tau病发病前，年轻人严重认知和行为缺陷的发展；4)tau蛋白的病理性磷酸化表位的存在，包括在S396/S404的特征性GSK-3 β基序。两种GSK-3同工酶在亲代APP-V717I淀粉样蛋白小鼠的大脑中都被激活，即使在认知和行为缺陷明显的幼年时也是如此，但在淀粉样蛋白出现之前。沉积。这些数据表明，淀粉样蛋白通过激活GSK-3诱导tau病变，并提示该激酶在维持成年神经元功能完整性方面的作用。
The hypothesis that amyloid pathology precedes and induces the tau pathology of Alzheimer's disease is experimentally supported hem through the identification of GSK-3 isozymes as a major link in the signaling pathway from amyloid to tau pathology. This study compares two novel bigenic mouse models: APP-V717I x Tau-P301L mice with combined amyloid and tau pathology and GSK-3 beta x Tau-P301L mice with tauopathy only. Extensive and remarkable parallels were observed between these strains including 1) aggravation of tauopathy with highly fibrillar tangles in the hippocampus and cortex, 2) prolonged survival correlated to alleviated brainstem tauopathy; 3) development of severe cognitive and behavioral defects in young adults before the onset of amyloid deposition or tauopathy, and 4) presence of pathological phosphoepitopes of tau, including the characteristic GSK-3 beta motif at S396/S404. Both GSK-3 isozymes were activated in the brain of parental APP-V717I amyloid mice, even at a young age when cognitive and behavioral defects are evident but before amyloid. deposition. The data indicate that amyloid induces tauopathy through activation of GSK-3 and suggest a role for the kinase in maintaining the functional integrity of adult neurons.