BACE1 deficiency causes altered neuronal activity and neurodegeneration.
BACE1 deficiency causes altered neuronal activity and neurodegeneration.
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DOI：
10.1523/jneurosci.1334-10.2010
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发表时间：
2010-06-30
期刊：
影响因子：
--
通讯作者：
Yan R
中科院分区：
文献类型：
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作者：
Hu X;Zhou X;He W;Yang J;Xiong W;Wong P;Wilson CG;Yan R
BACE 1是体内β-淀粉样蛋白（Aβ）释放所必需的，抑制BACE 1活性是减少阿尔茨海默病患者Aβ生成的目标。为了进一步了解BACE 1抑制剂在人类患者中的安全使用，我们旨在通过表征BACE 1缺失小鼠来研究BACE 1的生理功能。在这里，我们报告的自发行为癫痫发作的BACE 1基因敲除小鼠的发现。脑电图记录显示BACE 1基因敲除小鼠出现异常棘波放电，与野生型同窝小鼠相比，BACE 1基因敲除小鼠中红藻氨酸诱导的癫痫发作也更频繁。生化和形态学研究表明，轴突和表面水平的Nav1.2显着升高，在BACE 1-null小鼠，从BACE 1-null海马神经元记录的快钠通道电流增加一致。膜片钳记录也显示改变了孤立的BACE 1空海马神经元的固有放电特性。此外，在BACE 1-null脑切片中群体尖峰显著增加，表明BACE 1-null神经元的过度兴奋性。总之，我们的研究结果表明，增加钠通道活性有助于在BACE 1基因敲除小鼠中观察到的癫痫行为。本研究的结果对于开发BACE 1抑制剂治疗阿尔茨海默病和癫痫的应用研究至关重要。
BACE1 is required for the release of β–amyloid (Aβ) in vivo, and inhibition of BACE1 activity is targeted for reducing Aβ generation in Alzheimer's patients. In order to further our understanding of the safe use of BACE1 inhibitors in human patients, we aimed to study the physiological functions of BACE1 by characterizing BACE1–null mice. Here we report the finding of spontaneous behavioral seizures in BACE1–null mice. Electroencephalographic recordings revealed abnormal spike-wave discharges in BACE1–null mice, and kainic acid-induced seizures also occurred more frequently in BACE1–null mice compared to their wild-type littermates. Biochemical and morphological studies showed that axonal and surface levels of Nav1.2 were significantly elevated in BACE1–null mice, consistent with the increased fast sodium channel current recorded from BACE1–null hippocampal neurons. Patch-clamp recording also showed altered intrinsic firing properties of isolated BACE1–null hippocampal neurons. Furtherover, population spikes were significantly increased in BACE1–null brain slices, indicating hyperexcitability of BACE1–null neurons. Together, our results suggest that increased sodium channel activity contributes to the epileptic behaviors observed in BACE1–null mice. The knowledge from this study is crucial for the development of BACE1 inhibitors for Alzheimer's therapy and to the applicative study of epilepsy.