Zheng Chen, Geetha Thangiah, Gearing Marla, Babu Jeganathan Ramesh
Department of Nutrition, Dietetics and Hospitality Management, Auburn University, Auburn, Alabama, USA.
Department of Chemistry, Auburn University at Montgomery, Montgomery, Alabama, USA.
J Neurochem. 2015 Jun;133(6):919-25. doi: 10.1111/jnc.13076. Epub 2015 Mar 19.
Amyloid beta (Aβ) protein is the primary proteinaceous deposit found in the brains of patients with Alzheimer's disease (AD). Evidence suggests that Aβ plays a central role in the development of AD pathology. Here, we show in PC12 cells, Aβ impairs tropomyosin receptor kinase A (TrkA) ubiquitination, phosphorylation, and its association with p75(NTR), p62, and TRAF6 induced by nerve growth factor. The ubiquitination and tyrosine phosphorylation of TrkA was also found to be impaired in postmortem human AD hippocampus compared to control. Interestingly, the nitrotyrosylation of TrkA was increased in AD hippocampus and this explains why the phosphotyrosylation and ubiquitination of TrkA was impaired. In AD brain, the production of matrix metalloproteinase-7 (MMP-7), which cleaves proNGF, was reduced, thereby leading to the accumulation of pro-NGF and a decrease in the level of active NGF. TrkA signaling events, including Ras/MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways, are deactivated with Aβ and in the human AD hippocampus. Findings show that Aβ blocks the TrkA ubiquitination and downstream signaling similar to AD hippocampus. Cell survival and differentiation are essential for living organisms. We propose that under normal conditions, nerve growth factor (NGF) leads to Tropomyosin receptor kinase A (TrkA) phosphorylation, ubiquitination and its association with p75(NTR), p62 and TRAF6, thereby promoting cell survival and differentiation. In diseased conditions such as Alzheimer's, proNGF leads to nitrotyrosylation of TrkA, thereby impairing its ubiquitination and downstream signaling which results in apoptosis. TRAF6 = tumor necrosis factor receptor-associated factor 6; Ub = ubiquitin.
β淀粉样蛋白（Aβ）是在阿尔茨海默病（AD）患者大脑中发现的主要蛋白质沉积物。有证据表明，Aβ在AD病理学发展中起核心作用。在此，我们在PC12细胞中发现，Aβ会损害神经营养因子诱导的原肌球蛋白受体激酶A（TrkA）的泛素化、磷酸化及其与p75（NTR）、p62和TRAF6的结合。与对照组相比，在AD患者死后的海马体中也发现TrkA的泛素化和酪氨酸磷酸化受损。有趣的是，AD海马体中TrkA的硝基酪氨酸化增加，这解释了TrkA的磷酸酪氨酸化和泛素化受损的原因。在AD大脑中，裂解前体神经生长因子（proNGF）的基质金属蛋白酶-7（MMP-7）产生减少，从而导致pro-NGF积累和活性NGF水平降低。包括Ras/丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）途径在内的TrkA信号转导事件在Aβ作用下以及在人类AD海马体中被失活。研究结果表明，Aβ阻断TrkA泛素化和下游信号传导，类似于AD海马体。细胞存活和分化对生物体至关重要。我们提出，在正常情况下，神经营养因子（NGF）导致原肌球蛋白受体激酶A（TrkA）磷酸化、泛素化及其与p75（NTR）、p62和TRAF6结合，从而促进细胞存活和分化。在诸如阿尔茨海默病等疾病状态下，proNGF导致TrkA硝基酪氨酸化，从而损害其泛素化和下游信号传导，导致细胞凋亡。TRAF6 = 肿瘤坏死因子受体相关因子6；Ub = 泛素
