Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice
Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice
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DOI：
10.1074/jbc.m505249200
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发表时间：
2005-09-02
影响因子：
4.8
通讯作者：
De Strooper, B
中科院分区：
文献类型：
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作者：
Dominguez, D;Tournoy, J;De Strooper, B
β-分泌酶（BACE 1）是阿尔茨海默病中淀粉样β-肽（A β）生成的限速蛋白酶。据报道，bace 1基因失活的小鼠是健康的。然而，编码BACE 2的同源基因的存在提高了补偿机制的可能性。因此，我们已经产生了bace 1，bace 2和双敲除小鼠。我们在这里报告，BACE 1小鼠表现出复杂的表型。一个变量，但显着数量的BACE 1后代在出生后的第一周死亡。存活的小鼠仍然比同窝对照小鼠小，并表现出过度活跃的行为。在电生理学上，观察到BACE 1缺陷神经元中电压门控钠通道稳态失活的细微变化。相反，bace 2基因敲除小鼠表现出整体健康的表型。然而，BACE 2和BACE 1的联合缺陷增强了bace 1（-/-）致死表型。在生物化学水平上，我们已经证实BACE 1缺乏导致神经元中A β生成几乎完全阻断，但在神经胶质中则不然。由于神经胶质细胞在大脑中的含量是神经元的10倍，我们的数据表明BACE 2确实有助于阿尔茨海默病患者，特别是唐氏综合征患者大脑中的A β生成。总之，我们的数据挑战了BACE 1作为安全药物靶点的一般想法，并在声称阻断BACE 1活性不会产生重大副作用时需要谨慎。
beta-Secretase (BACE1) is the rate-limiting protease for the generation of the amyloid beta-peptide (A beta) in Alzheimer disease. Mice in which the bace1 gene is inactivated are reported to be healthy. However, the presence of a homologous gene encoding BACE2 raises the possibility of compensatory mechanisms. Therefore, we have generated bace1, bace2, and double knockout mice. We report here that BACE1 mice display a complex phenotype. A variable but significant number of BACE1 offspring died in the first weeks after birth. The surviving mice remained smaller than their littermate controls and presented a hyperactive behavior. Electrophysiologically, subtle alterations in the steady-state inactivation of voltage-gated sodium channels in BACE1-deficient neurons were observed. In contrast, bace2 knockout mice displayed an overall healthy phenotype. However, a combined deficiency of BACE2 and BACE1 enhanced the bace1(-/-) lethality phenotype. At the biochemical level, we have confirmed that BACE1 deficiency results in an almost complete block of A beta generation in neurons, but not in glia. As glia are 10 times more abundant in brain compared with neurons, our data indicate that BACE2 could indeed contribute to A beta generation in the brains of Alzheimer disease and, in particular, Down syndrome patients. In conclusion, our data challenge the general idea of BACE1 as a safe drug target and call for some caution when claiming that no major side effects should be expected from blocking BACE1 activity.