Cerebrospinal fluid neprilysin is reduced in prodromal Alzheimer's disease
Cerebrospinal fluid neprilysin is reduced in prodromal Alzheimer's disease
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DOI：
10.1002/ana.20494
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发表时间：
2005-06-01
影响因子：
11.2
通讯作者：
Sasaki, H
中科院分区：
文献类型：
--
作者：
Maruyama, M;Higuchi, M;Sasaki, H
淀粉样蛋白β肽（A β）作为病理级联反应的起始物与阿尔茨海默病（AD）有关。一些令人信服的证据支持A β降解酶脑啡肽酶在散发性AD发病机制中的主要作用。在这里，我们已经表明，与年龄匹配的对照组相比，AD转换的轻度认知障碍和早期AD患者的脑脊液（CSF）脑啡肽酶活性（CSF-NEP）显著降低。改变的CSF-NEP可能反映了神经元脑啡肽酶的变化，因为通过将携带脑啡肽酶的病毒载体注射到脑啡肽酶缺陷小鼠的脑中证明了脑啡肽酶从脑组织转移到CSF中。有趣的是，CSF-NEP随着AD的进展而升高。沿着CSF-NEP与CSFtau蛋白的密切关联，这一发现表明突触前定位的脑啡肽酶可以作为突触破坏的结果释放到CSF中。神经元损伤对CSF-NEP的影响进一步通过在表现出红藻氨酸诱导的神经变性的大鼠中CSF-NEP的显著增加来证明。我们的研究结果明确地表明CSF-NEP作为生物化学指标的意义，以追求涉及脑啡肽酶活性降低和A β诱导的突触毒性的病理过程，并支持脑啡肽酶上调在改善前驱期和早期AD的神经病理学中的潜在益处。
Amyloid beta peptide (A beta) has been implicated in Alzheimer's disease (AD) as an initiator of the pathological cascades. Several lines of compelling evidence have supported major roles of A beta-degrading enzyme neprilysin in the pathogenesis of sporadic AD. Here, we have shown a substantial reduction of cerebrospinal fluid (CSF) neprilysin activity (CSF-NEP) in patients with AD-converted mild cognitive impairment and early AD as compared with age-matched control subjects. The altered CSF-NEP likely reflects changes in neuronal neprilysin, since transfer of neprilysin from brain tissue into CSF was demonstrated by injecting neprilysin-carrying viral vector into the brains of neprilysin-deficient mice. Interestingly, CSF-NEP showed an elevation with the progression of AD. Along with a close association of CSF-NEP with CSF tau proteins, this finding suggests that presynaptically located neprilysin can be released into CSF as a consequence of synaptic disruption. The impact of neuronal damages on CSF-NEP was further demonstrated by a prominent increase of CSF-NEP in rats exhibiting kainate-induced neurodegeneration. Our results unequivocally indicate significance of CSF-NEP as a biochemical indicator to pursue a pathological process that involves decreased neprilysin activity and A beta-induced synaptic toxicity, and the support the potential benefits of neprilysin up-regulation in ameliorating neuropathology in prodromal and early AD.