Mass General Institute of Neurodegenerative Disease, Dept. of Neurology, Harvard Medical School , Boston, MA, USA.
Sci Rep. 2012;2:231. doi: 10.1038/srep00231. Epub 2012 Jan 20.
The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is necessary to generate the Aβ peptide, which is implicated in Alzheimer's disease pathology. Studies show that the expression of BACE1 and its protease activity are tightly regulated, but the physiological function of BACE1 remains poorly understood. Recently, numerous axon guidance proteins were identified as potential substrates of BACE1. Here, we examined the consequences of loss of BACE1 function in a well-defined in vivo model system of axon guidance, mouse olfactory sensory neurons (OSNs). The BACE1 protein resides predominantly in proximal segment and the termini of OSN axons, and the expression of BACE1 inversely correlates with odor-evoked neural activity. The precision of targeting of OSN axons is disturbed in both BACE1 null and, surprisingly, in BACE1 heterozygous mice. We propose that BACE1 cleavage of axon guidance proteins is essential to maintain the connectivity of OSNs in vivo.
β-淀粉样前体蛋白裂解酶 1（BACE1）对于生成与阿尔茨海默病病理相关的 Aβ肽是必需的。研究表明，BACE1 的表达及其蛋白酶活性受到严格调控，但 BACE1 的生理功能仍知之甚少。最近，许多轴突导向蛋白被鉴定为 BACE1 的潜在底物。在这里，我们在轴突导向的明确体内模型系统中研究了 BACE1 功能丧失的后果，即小鼠嗅觉感觉神经元（OSN）。BACE1 蛋白主要存在于 OSN 轴突的近端段和末端，BACE1 的表达与气味诱发的神经活动呈负相关。OSN 轴突的靶向精度在 BACE1 缺失和令人惊讶的 BACE1 杂合子小鼠中均受到干扰。我们提出，BACE1 对轴突导向蛋白的裂解对于维持 OSN 在体内的连接性是必不可少的。
