BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions
BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions
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DOI：
10.1523/jneurosci.2766-05.2005
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发表时间：
2005-12-14
影响因子：
5.3
通讯作者：
Wong, PC
中科院分区：
文献类型：
--
作者：
Laird, FM;Cai, HB;Wong, PC
一种被称为β-位点APP裂解酶1（BACE1）的跨膜天冬氨酰蛋白酶可裂解在神经元中大量存在的淀粉样β前体蛋白（APP），它是产生与阿尔茨海默病（AD）发病机制有关的淀粉样β（Aβ）肽所必需的。我们现在证明，在中枢神经系统神经元中富集的BACE1是使大脑易于发生Aβ淀粉样变性的一个主要决定因素。神经元中生理水平较高的BACE1活性，以及较低水平的BACE2和α-分泌酶的抗淀粉样生成活性，是中枢神经系统中Aβ积累的主要原因，而其他器官则不受影响。重要的是，在APPswe；PS1ΔE9小鼠中缺失BACE1可防止在这种Aβ淀粉样变性模型中出现的Aβ沉积和与年龄相关的认知异常。此外，Aβ沉积物对BACE1的剂量敏感，当BACE1被沉默时，Aβ可从中枢神经系统中有效清除。然而，BACE1基因敲除小鼠表现出海马突触可塑性以及认知和情绪测试表现的改变。重要的是，在BACE1（-/-）小鼠中，通过共表达APPswe；PS1ΔE9转基因可防止记忆缺陷，但不能防止情绪改变，这表明BACE1的其他潜在底物可能影响与情绪相关的神经回路。我们的研究结果确定BACE1和APP加工途径对认知、情绪和突触功能至关重要，未来的研究应警惕为改善AD中Aβ淀粉样变性而设计的BACE1抑制剂可能出现的基于机制的潜在副作用。
A transmembrane aspartyl protease termed beta-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-beta precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-beta(A beta) peptides implicated in the pathogenesis of Alzheimer's disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to A beta amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and alpha-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of A beta in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1 Delta E9 mice prevents both A beta deposition and age-associated cognitive abnormalities that occur in this model of A beta amyloidosis. Moreover, A beta deposits are sensitive to BACE1 dosage and can be efficiently cleared from the CNS when BACE1 is silenced. However, BACE1 null mice manifest alterations in hippocampal synaptic plasticity as well as in performance on tests of cognition and emotion. Importantly, memory deficits but not emotional alterations in BACE1(-/-) mice are prevented by coexpressing APPswe;PS1 Delta E9 transgenes, indicating that other potential substrates of BACE1 may affect neural circuits related to emotion. Our results establish BACE1 and APP processing pathways as critical for cognitive, emotional, and synaptic functions, and future studies should be alert to potential mechanism-based side effects that may occur with BACE1 inhibitors designed to ameliorate A beta amyloidosis in AD.