β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects
β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects
复制标题
DOI：
10.1074/jbc.m112.415505
复制
发表时间：
2012-11-09
影响因子：
4.8
通讯作者：
Vassar, Robert
中科院分区：
文献类型：
--
作者：
Hitt, Brian;Riordan, Sean M.;Vassar, Robert
BACE 1是一种β-分泌酶，可启动与阿尔茨海默病有关的β-淀粉样肽的产生。然而，人们对BACE 1的功能知之甚少。BACE 1缺陷小鼠表现出轻度但复杂的神经学表型，表明治疗性BACE 1抑制可能不完全没有基于机制的副作用。最近，我们报道了BACE 1基因敲除小鼠在嗅球中嗅感觉神经元向肾小球的投射中存在轴突导向缺陷。在这里，我们发现BACE 1缺乏也会导致海马中轴突引导缺陷，即从齿状回到CA 3的苔藓纤维投射的锥体下束缩短和紊乱。虽然我们观察到经典的轴突导向分子EphA 4在HEK 293细胞中与BACE 1共表达时被BACE 1切割，但我们没有发现BACE 1在脑中加工EphA 4的证据。值得注意的是，我们发现BACE 1（-/-）小鼠的轴突导向缺陷与最近发现的BACE 1底物缺陷小鼠的轴突导向缺陷惊人地相似，BACE 1底物是参与神经突生长的L1（CHL 1）的神经细胞粘附分子密切同源物。CHL 1在BACE 1（-/-）中经历BACE 1依赖性加工，但在BACE 1（-/-）、海马和嗅球中不经历BACE 1依赖性加工，表明CHL 1是体内BACE 1底物。最后，BACE 1和CHL 1共定位于海马苔藓纤维、嗅觉感觉神经元轴突和原代海马神经元生长锥的末端。我们得出结论，BACE 1（-/-）轴突导向缺陷可能是废除BACE 1处理CHL 1的结果，BACE 1缺陷产生CHL 1功能丧失表型。我们的研究结果意味着轴突错误靶向的可能性，可能会发生在成年神经源性和/或再生神经元作为慢性BACE 1抑制的结果，并添加注意BACE 1抑制剂的发展。
BACE1 is the beta-secretase enzyme that initiates production of the beta-amyloid peptide involved in Alzheimer disease. However, little is known about the functions of BACE1. BACE1-deficient mice exhibit mild but complex neurological phenotypes suggesting therapeutic BACE1 inhibition may not be completely free of mechanism-based side effects. Recently, we have reported that BACE1 null mice have axon guidance defects in olfactory sensory neuron projections to glomeruli in the olfactory bulb. Here, we show that BACE1 deficiency also causes an axon guidance defect in the hippocampus, a shortened and disorganized infrapyramidal bundle of the mossy fiber projection from the dentate gyrus to CA3. Although we observed that a classical axon guidance molecule, EphA4, was cleaved by BACE1 when co-expressed with BACE1 in HEK293 cells, we could find no evidence of BACE1 processing of EphA4 in the brain. Remarkably, we discovered that the axon guidance defects of BACE1(-/-) mice were strikingly similar to those of mice deficient in a recently identified BACE1 substrate, the neural cell adhesion molecule close homolog of L1 (CHL1) that is involved in neurite outgrowth. CHL1 undergoes BACE1-dependent processing in BACE1(-/-), but not BACE1(-/-), hippocampus, and olfactory bulb, indicating that CHL1 is a BACE1 substrate in vivo. Finally, BACE1 and CHL1 co-localize in the terminals of hippocampal mossy fibers, olfactory sensory neuron axons, and growth cones of primary hippocampal neurons. We conclude that BACE1(-/-) axon guidance defects are likely the result of abrogated BACE1 processing of CHL1 and that BACE1 deficiency produces a CHL1 loss-of-function phenotype. Our results imply the possibility that axon mis-targeting may occur in adult neurogenic and/or regenerating neurons as a result of chronic BACE1 inhibition and add a note of caution to BACE1 inhibitor development.