High β-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-β levels -: Implications for the treatment of Alzheimer disease
High β-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-β levels -: Implications for the treatment of Alzheimer disease
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DOI：
10.1074/jbc.m507016200
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发表时间：
2005-09-23
影响因子：
4.8
通讯作者：
Masliah, E
中科院分区：
文献类型：
--
作者：
Rockenstein, E;Mante, M;Masliah, E
β - 淀粉样肽（Aβ）被广泛假定在阿尔茨海默病中起因果作用。Aβ从淀粉样前体蛋白（APP）释放需要β - 位点APP裂解酶（BACE1）进行蛋白水解。尽管阿尔茨海默病大脑和人（h）BACE1转基因（tg）小鼠中BACE1活性增加导致APP裂解改变，但这些分子改变对神经退行性变的作用尚不清楚。因此，我们利用鼠甲状腺1（Thy1）启动子在转基因小鼠的神经元中高水平表达hBACE1，同时表达或不表达hAPP。与hAPP小鼠相比，hBACE1/hAPP双转基因小鼠的APP C - 末端片段（C89、C83）水平升高，而全长APP和Aβ水平降低。与非转基因对照和hAPP小鼠相反，hBACE1小鼠和hBACE1/hAPP小鼠在新皮质和海马中出现神经元退变以及髓鞘降解。hBACE1和hBACE1/hAPP小鼠的神经功能缺陷也比hAPP小鼠更严重。这些结果表明，高水平的BACE1活性足以在体内引发神经退行性变和神经功能下降。这种致病途径涉及APP C - 末端片段的积累，但不依赖于人Aβ产量的增加。因此，抑制BACE1可能不仅阻断Aβ依赖性的，而且阻断Aβ非依赖性的致病机制。
Amyloid-beta peptides (A beta) are widely presumed to play a causal role in Alzheimer disease. Release of A beta from the amyloid precursor protein (APP) requires proteolysis by the beta-site APP-cleaving enzyme (BACE1). Although increased BACE1 activity in Alzheimer disease brains and human ( h) BACE1 transgenic (tg) mice results in altered APP cleavage, the contribution of these molecular alterations to neurodegeneration is unclear. We therefore used the murine Thy1 promoter to express high levels of hBACE1, with or without hAPP, in neurons of tg mice. Compared with hAPP mice, hBACE1/hAPP doubly tg mice had increased levels of APP C-terminal fragments (C89, C83) and decreased levels of full-length APP and A beta. In contrast to non-tg controls and hAPP mice, hBACE1 mice and hBACE1/hAPP mice showed degeneration of neurons in the neocortex and hippocampus and degradation of myelin. Neurological deficits were also more severe in hBACE1 and hBACE1/hAPP mice than in hAPP mice. These results demonstrate that high levels of BACE1 activity are sufficient to elicit neurodegeneration and neurological decline in vivo. This pathogenic pathway involves the accumulation of APP C-terminal fragments but does not depend on increased production of human A beta. Thus, inhibiting BACE1 may block not only A beta-dependent but also A beta-independent pathogenic mechanisms.