J Neurosci：大脑中NGF释放过程被阐明

麦吉尔大学医学院药理学和药物治疗学系博士A. Claudio Cuello领导的研究小组了解了脑细胞衰退对阿尔茨海默氏病（AD）很敏感后，发现了其中一个关键过程。这项研究发表在《神经科学杂志》上的研究表明该研究发现有利于开发AD替代疗法。

大脑的神经元之间的沟通打破被认为有助于患AD的人减缓记忆丢失和认知功能丧失。猜测其中原因就是神经生长因子NGF，NGF负责产生能维持供养健康的胆碱能神经元（在整个生命周期对AD都特别敏感的一类脑细胞）的信号分子。奇怪的是为了解释AD患者中胆碱能神经元变性，科学家们从来没有发现这种神经生长因子NGF存在异常。

然而这项新的研究阐明了大脑中NGF的释放过程，以活性形式成熟并最终退化。研究人员还确定在AD中这一进程是如何改变的。研究小组证明健康成年大鼠接受能抑制活性NGF的成熟过程的药物治疗后，结果导致AD样胆碱能功能单元的缺失，AD样胆碱能功能单元的缺失会导致认知功能障碍。相反，当给予防止活跃的神经生长因子退化的药物后，胆碱能功能单元之间的接触显着增加。

这项研究的首席作者、麦吉尔大学的博士后研究员Simon Allard博士解释说：“由于受到区分神经生长因子活性和非活性形式的相关技术挑战，了解这一机制还存在部分困难。但我们提出的操作方法与现有的旨在保护神经元变性的治疗方法不同”。

作者认为这些发现提示将来用药物治疗就可延缓阿尔茨海默氏病的进展。Charles E. Frosst/Merck公司主席Cuello博士认为这一发现有助于设计AD替代疗法。

这项研究经费部分由加拿大卫生研究院（CIHR）资助。 (生物谷 Bioon.com)

doi:10.1523/JNEUROSCI.1144-11.2012
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Impact of the NGF Maturation and Degradation Pathway on the Cortical Cholinergic System Phenotype

Simon Allard1, Wanda C. Leon1, Prateep Pakavathkumar1, Martin A. Bruno4, Alfredo Ribeiro-da-Silva1,2,*, and A. Claudio Cuello1,2,3,*

Cortical cholinergic atrophy plays a significant role in the cognitive loss seen with aging and in Alzheimer's disease (AD), but the mechanisms leading to it remain unresolved. Nerve growth factor (NGF) is the neurotrophin responsible for the phenotypic maintenance of basal forebrain cholinergic neurons in the mature and fully differentiated CNS. In consequence, its implication in cholinergic atrophy has been suspected; however, no mechanistic explanation has been provided. We have previously shown that the precursor of NGF (proNGF) is cleaved extracellularly by plasmin to form mature NGF (mNGF) and that mNGF is degraded by matrix metalloproteinase 9. Using cognitive-behavioral tests, Western blotting, and confocal and electron microscopy, this study demonstrates that a pharmacologically induced chronic failure in extracellular NGF maturation leads to a reduction in mNGF levels, proNGF accumulation, cholinergic degeneration, and cognitive impairment in rats. It also shows that inhibiting NGF degradation increases endogenous levels of the mature neurotrophin and increases the density of cortical cholinergic boutons. Together, the data point to a mechanism explaining cholinergic loss in neurodegenerative conditions such as AD and provide a potential therapeutic target for the protection or restoration of this CNS transmitter system in aging and AD.