Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ, USA.
J Alzheimers Dis. 2010;19(2):621-30. doi: 10.3233/JAD-2010-1253.
We reported that tumor necrosis factor receptor I (TNFRI) is required for neuronal death induced by amyloid-beta protein in the Alzheimer's disease (AD) brain. However, whether TNF receptor subtypes are expressed and activated differentially in AD brains compared to non-demented brains remains unclear. Our studies on Western blot and ELISA measurements demonstrated that TNFRI levels are increased whereas TNFRII levels are decreased in AD brains compared to non-demented brains (p <0.05). Immunohistochemical results demonstrated that both TNFRI and TNFRII are expressed in neurons in AD and non-demented brains. However, in situ hybridization studies showed little change in the mRNA levels of either type of TNF receptor in the neurons of AD brains compared to non-demented brains. To examine whether different levels of TNF receptors in AD brains are correlated with the alteration of functional binding of TNF receptors, by using 125I-TNF-alpha binding technique, we found that, in AD brains, 125I-TNF-alpha binding affinity to TNFRI is increased, whereas binding affinity to TNFRII is decreased (p < 0.01). These studies reveal a novel observation of abnormal TNF receptor activation in AD brains. Differential TNF receptor protein levels and binding affinities suggest distinct pathogenic mechanisms of neurodegeneration in the AD brain.
我们曾报道，肿瘤坏死因子受体 I（TNFRI）在阿尔茨海默病（AD）脑内淀粉样β蛋白诱导的神经元死亡中发挥作用。然而，与非痴呆脑相比，AD 脑中 TNF 受体亚型的表达和激活是否存在差异尚不清楚。我们的 Western blot 和 ELISA 测量研究表明，与非痴呆脑相比，AD 脑中 TNFRI 水平升高，而 TNFRII 水平降低（p<0.05）。免疫组织化学结果表明，TNFRI 和 TNFRII 均在 AD 和非痴呆脑的神经元中表达。然而，原位杂交研究显示，与非痴呆脑相比，AD 脑神经元中两种 TNF 受体的 mRNA 水平几乎没有变化。为了研究 AD 脑中不同水平的 TNF 受体是否与 TNF 受体功能结合的改变相关，我们使用 125I-TNF-α结合技术发现，在 AD 脑中，125I-TNF-α与 TNFRI 的结合亲和力增加，而与 TNFRII 的结合亲和力降低（p<0.01）。这些研究揭示了 AD 脑中 TNF 受体异常激活的新观察结果。TNF 受体蛋白水平和结合亲和力的差异提示 AD 脑中神经退行性变的不同发病机制。
