Koliatsos V E, Clatterbuck R E, Nauta H J, Knüsel B, Burton L E, Hefti F F, Mobley W C, Price D L
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2181.
Ann Neurol. 1991 Dec;30(6):831-40. doi: 10.1002/ana.410300613.
Basal forebrain cholinergic neurons respond to nerve growth factor (NGF), and it has been suggested that the administration of NGF might prevent their degeneration in patients with Alzheimer's disease. One major prerequisite to be fulfilled before the consideration of clinical trials of NGF in patients with Alzheimer's disease is the demonstration that human NGF affects basal forebrain cholinergic neurons in primates. In the present study, we used a recombinant human nerve growth factor (rhNGF), which we previously showed to be active on rat basal forebrain cholinergic neurons, in nonhuman primates with a unilateral transection of the fornix (a well-established model for the induction of retrograde degenerative changes in septal cholinergic neurons). After the lesion, one group of animals received rhNGF and a second group received vehicle solution for 2 weeks. In animals receiving vehicle, the medial septal nucleus ipsilateral to the lesion showed reductions in number (55%) and size of cell bodies immunoreactive for NGF receptor and choline acetyltransferase. In Nissl stains, many cells showed reduced size and basophilia. The rhNGF completely prevented alterations in the number and size of NGF receptor- and choline acetyltransferase-immunoreactive neurons in the medial septal nucleus and reversed atrophy in a subpopulation of large, basophilic medial septal nucleus neurons, as identified by Nissl stains. The effects of rhNGF were identical to those of mouse NGF, which we have previously used in the same primate lesion paradigm. The restoration of the phenotype of injured cholinergic septal neurons by rhNGF in the monkey raises the possibility that this factor may be used to ameliorate acetylcholine-dependent memory impairments that occur in aged nonhuman primates. In concert, results of the present investigation provide critical information for the future use of NGF in patients with neurological disorders that affect NGF-responsive cells in the peripheral and central nervous systems.
基底前脑胆碱能神经元对神经生长因子（NGF）有反应，有人提出给予NGF可能会预防阿尔茨海默病患者的神经元退化。在考虑对阿尔茨海默病患者进行NGF临床试验之前，需要满足的一个主要前提是证明人NGF对灵长类动物的基底前脑胆碱能神经元有影响。在本研究中，我们在单侧穹窿横断的非人灵长类动物（这是诱导隔区胆碱能神经元逆行性退行性变化的成熟模型）中使用了重组人神经生长因子（rhNGF），我们之前已证明该因子对大鼠基底前脑胆碱能神经元有活性。损伤后，一组动物接受rhNGF，另一组接受赋形剂溶液，持续2周。在接受赋形剂的动物中，损伤同侧的内侧隔核中，对NGF受体和胆碱乙酰转移酶免疫反应阳性的细胞数量减少了55%，细胞体大小也减小。在尼氏染色中，许多细胞显示大小减小和嗜碱性降低。rhNGF完全阻止了内侧隔核中NGF受体和胆碱乙酰转移酶免疫反应阳性神经元数量和大小的改变，并逆转了尼氏染色所确定的一部分大的嗜碱性内侧隔核神经元的萎缩。rhNGF的作用与我们之前在相同灵长类动物损伤模型中使用的小鼠NGF的作用相同。rhNGF使猴体内受损胆碱能隔区神经元的表型得以恢复，这增加了该因子可用于改善老年非人灵长类动物中出现的乙酰胆碱依赖性记忆障碍的可能性。同时，本研究结果为未来在影响外周和中枢神经系统中NGF反应性细胞的神经疾病患者中使用NGF提供了关键信息。
