Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Neurochem Res. 2012 Jun;37(6):1256-60. doi: 10.1007/s11064-012-0770-9. Epub 2012 Apr 8.
In this mini-review I summarize our research efforts in ascertaining the possible neuro-reparative properties of the GM1 ganglioside and its cooperative effects with NGF in stroke-lesion models. We also review aspects of our NGF investigations which have recently led to the discovery that NGF is released in an activity-dependent manner in the form of its precursor molecule, proNGF. These studies support the notion that in the CNS NGF metabolism conversion and degradation occur in the extracellular milieu. We have also validated this pathway in vivo demonstrating that the pharmacological inhibition of the pro-to mature NGF conversion results in the brain accumulation of proNGF and loss and atrophy of cortical cholinergic synapses. Furthermore, we have gathered neurochemical evidence for a compromise of this newly discovered NGF metabolic pathway in Alzheimer's disease, explaining the vulnerability of NGF-dependent forebrain cholinergic neurons in this disease despite normal NGF synthesis and abundance of NGF precursor.
在这篇迷你综述中，我总结了我们在确定 GM1 神经节苷脂的可能神经修复特性及其与 NGF 在中风损伤模型中的协同作用方面的研究成果。我们还回顾了我们最近关于 NGF 研究的一些方面，这些研究发现 NGF 以其前体分子 proNGF 的形式以活性依赖的方式释放。这些研究支持这样一种观点，即在中枢神经系统中，NGF 的代谢转换和降解发生在细胞外环境中。我们还在体内验证了这条途径，证明了前体到成熟 NGF 转化的药理学抑制会导致脑内 proNGF 的积累以及皮质胆碱能突触的丧失和萎缩。此外，我们还收集了神经化学证据，证明在阿尔茨海默病中，这条新发现的 NGF 代谢途径受到了损害，尽管 NGF 合成正常且 NGF 前体丰富，但仍导致了依赖于 NGF 的前脑胆碱能神经元易损性。
