Salehi A, Ocampo M, Verhaagen J, Swaab D F
Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, Amsterdam, The Netherlands.
Exp Neurol. 2000 Jan;161(1):245-58. doi: 10.1006/exnr.1999.7252.
In a previous study we showed that the staining of tyrosine kinase receptors (trks), which are high-affinity neurotrophin receptors (NTRs), is strongly diminished in the nucleus basalis of Meynert (NBM) of Alzheimer's disease (AD) patients, which may explain the lack of effect of NGF therapy in AD patients so far. Since the literature regarding the expression of low-affinity NTRs was rather controversial, the aim of the present study was to examine (i) possible changes in the staining of low-affinity NTRs, i.e., p75 in the human NBM, an area that is severely affected in AD; and (ii) alterations of these receptors in relation to risk factors for AD, e. g., age, sex, and menopause. Brain material of 31 controls and 30 AD patients was obtained at autopsy, embedded in paraffin, and stained immunocytochemically. Using an image analysis system, we quantified p75 immunoreactivity in both cell bodies and fibers at the level of the NBM. Our results showed a significant diminishment of p75 immunoreactivity in both cell bodies and fibers of NBM neurons in AD. We did not find any relationship between age or sex and the expression of p75 receptor in cell bodies. However, there was a clearly positive relationship between age and fiber staining in AD patients which suggests the occurrence of a p75 transport disorder as an early event in the process of AD. These observations and the earlier reported decreased staining of trk receptors show that degeneration of NBM neurons in AD is associated with a decreased neurotrophin responsiveness of NBM neurons in AD and that therapeutic strategies should be directed toward upregulation of receptors or facilitation of transport before an effect of neurotrophins in AD may be expected.
在先前的一项研究中，我们发现酪氨酸激酶受体（trks）的染色明显减少，trks是高亲和力神经营养因子受体（NTRs），在阿尔茨海默病（AD）患者的Meynert基底核（NBM）中减少，这可能解释了迄今为止NGF治疗对AD患者无效的原因。由于关于低亲和力NTRs表达的文献存在相当大的争议，本研究的目的是检查（i）低亲和力NTRs，即人类NBM中p75的染色可能发生的变化，NBM是AD中受严重影响的区域；以及（ii）这些受体与AD危险因素，如年龄、性别和绝经的关系。在尸检时获取31名对照者和30名AD患者的脑材料，石蜡包埋，并进行免疫细胞化学染色。使用图像分析系统，我们在NBM水平对细胞体和纤维中的p75免疫反应性进行了定量。我们的结果显示，AD患者NBM神经元的细胞体和纤维中p75免疫反应性均显著降低。我们未发现年龄或性别与细胞体中p75受体表达之间存在任何关系。然而，AD患者的年龄与纤维染色之间存在明显的正相关，这表明p75转运障碍的发生是AD过程中的早期事件。这些观察结果以及先前报道的trk受体染色减少表明，AD中NBM神经元的退化与AD中NBM神经元神经营养因子反应性降低有关，并且在预期神经营养因子对AD有作用之前，治疗策略应针对受体的上调或转运的促进。
