The Alzheimer's β-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb.
The Alzheimer's β-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb.
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DOI：
10.1186/1750-1326-6-88
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发表时间：
2011-12-28
影响因子：
15.1
通讯作者：
Vassar R
中科院分区：
文献类型：
--
作者：
Rajapaksha TW;Eimer WA;Bozza TC;Vassar R
β - 分泌酶，即β - 位点淀粉样前体蛋白裂解酶1（BACE1），是降低阿尔茨海默病（AD）患者大脑β - 淀粉样蛋白（Aβ）水平的主要治疗靶点。BACE1抑制剂的临床开发正在大力推进。然而，人们对BACE1的生理功能知之甚少，而且存在BACE1抑制可能导致基于机制的副作用的可能性。事实上，BACE1基因敲除（BACE1 - / -）小鼠表现出复杂的神经表型。有趣的是，BACE1与突触前神经元标志物共定位，表明其在轴突和/或轴突终末中起作用。此外，近期研究表明轴突导向分子是BACE1的潜在底物。在此，我们采用一种遗传学方法来研究BACE1在嗅感觉神经元（OSN）轴突导向中的功能，嗅感觉神经元是体内轴突靶向的一个研究较为深入的模型。
我们将BACE1 - / -小鼠与基因靶向小鼠进行交配，在这些基因靶向小鼠中，绿色荧光蛋白（GFP）从两个气味受体（OR）基因座（MOR23和M72）以及嗅标记蛋白（OMP）基因座表达，以产生MOR23 - GFP、M72 - GFP或OMP - GFP杂合子后代，这些后代要么是BACE1 + / +，要么是BACE1 - / -。BACE1 - / -小鼠的嗅球（OB）比BACE1 + / +小鼠的嗅球更小且重量更轻。在野生型小鼠中，BACE1存在于嗅球 glomeruli中的嗅感觉神经元轴突终末。在整装标本和组织切片中，与野生型glomeruli相比，许多来自OMP - GFP；BACE1 - / -小鼠的嗅球glomeruli畸形。MOR23 - GFP；BACE1 - / -小鼠具有不规则的MOR23 glomerulus，与BACE1 + / +小鼠相比，其受到随机定向、束状结构差的嗅感觉神经元轴突的神经支配。最重要的是，M72 - GFP；BACE1 - / -小鼠表现出M72嗅感觉神经元轴突错误靶向到异位glomeruli，这表明BACE1 - / -小鼠的轴突导向受损。
我们的研究结果表明，BACE1是嗅感觉神经元轴突准确靶向以及嗅球中glomeruli正确形成所必需的，这提示BACE1在轴突导向中起作用。嗅感觉神经元不断进行再生，因此需要持续的轴突导向。神经发生以及神经元和轴突的再生也发生在其他成年外周和中枢神经元群体中，这些神经元群体在整个生命过程中也需要轴突导向。因此，正在开发用于治疗AD的BACE1抑制剂可能也会潜在地导致这些神经元群体中的轴突靶向缺陷。
The β-secretase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), is a prime therapeutic target for lowering cerebral β-amyloid (Aβ) levels in Alzheimer's disease (AD). Clinical development of BACE1 inhibitors is being intensely pursued. However, little is known about the physiological functions of BACE1, and the possibility exists that BACE1 inhibition may cause mechanism-based side effects. Indeed, BACE1-/- mice exhibit a complex neurological phenotype. Interestingly, BACE1 co-localizes with presynaptic neuronal markers, indicating a role in axons and/or terminals. Moreover, recent studies suggest axon guidance molecules are potential BACE1 substrates. Here, we used a genetic approach to investigate the function of BACE1 in axon guidance of olfactory sensory neurons (OSNs), a well-studied model of axon targeting in vivo. We bred BACE1-/- mice with gene-targeted mice in which GFP is expressed from the loci of two odorant-receptors (ORs), MOR23 and M72, and olfactory marker protein (OMP) to produce offspring that were heterozygous for MOR23-GFP, M72-GFP, or OMP-GFP and were either BACE1+/+ or BACE1-/-. BACE1-/- mice had olfactory bulbs (OBs) that were smaller and weighed less than OBs of BACE1+/+ mice. In wild-type mice, BACE1 was present in OSN axon terminals in OB glomeruli. In whole-mount preparations and tissue sections, many OB glomeruli from OMP-GFP; BACE1-/- mice were malformed compared to wild-type glomeruli. MOR23-GFP; BACE1-/- mice had an irregular MOR23 glomerulus that was innervated by randomly oriented, poorly fasciculated OSN axons compared to BACE1+/+ mice. Most importantly, M72-GFP; BACE1-/- mice exhibited M72 OSN axons that were mis-targeted to ectopic glomeruli, indicating impaired axon guidance in BACE1-/- mice. Our results demonstrate that BACE1 is required for the accurate targeting of OSN axons and the proper formation of glomeruli in the OB, suggesting a role for BACE1 in axon guidance. OSNs continually undergo regeneration and hence require ongoing axon guidance. Neurogenesis and the regeneration of neurons and axons occur in other adult populations of peripheral and central neurons that also require axon guidance throughout life. Therefore, BACE1 inhibitors under development for the treatment of AD may potentially cause axon targeting defects in these neuronal populations as well.
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DOI：
10.1523/jneurosci.3657-09.2009
发表时间：
2009-10-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Vassar R;Kovacs DM;Yan R;Wong PC
通讯作者：
Wong PC
影响因子：
5.3
作者：
Laird, FM;Cai, HB;Wong, PC
通讯作者：
Wong, PC
影响因子：
64.5
作者：
Mombaerts, P;Wang, F;Axel, R
通讯作者：
Axel, R
影响因子：
64.5
作者：
VASSAR, R;NGAI, J;AXEL, R
通讯作者：
AXEL, R
影响因子：
3.5
作者：
Hussain, I;Powell, D;Christie, G
通讯作者：
Christie, G