Department of Pediatrics and the Center for Neural Disease and Degeneration, University of Rochester Medical Center, Rochester, NY 14642, USA.
Oxid Med Cell Longev. 2009 Sep-Oct;2(4):238-46. doi: 10.4161/oxim.2.4.9745.
The p75 neurotrophin receptor (p75NTR) is an alpha- and gamma-secretase substrate expressed preferentially in the cholinergic neurons of the nucleus basalis of Meynert, the hippocampus, and the cerebellum of the adult brain. Mutations of the gamma-secretase, presenilin, have been implicated in familial Alzheimer's disease. Furthermore, oxidative and inflammatory injury to the cholinergic neurons of the nucleus basalis of Meynert and hippocampus plays a critical role in the pathology of Alzheimer's disease. The intracellular domain of p75NTR (p75ICD) is the alpha- and gamma-secretase cleavage fragment of the holoreceptor that functions as an antioxidant in PC12 rat pheochromocytoma cells. Phosphorylation of the receptor is thought to be necessary for many of its functions, and two tyrosines in p75ICD have been among the functionally important phosphorylation sites. Site-directed mutagenesis was used to generate three p75ICD mutants that cannot be phosphorylated at either or both tyrosines, respectively. Each of these mutants was expressed in p75NTR-deficient PC12 cells to determine the effects of blocking phosphorylation at specific sites on the antioxidant activity of p75ICD. Interfering with phosphorylation at tyrosine-337 impairs antioxidant function, while interfering with phosphorylation at tyrosine-366 does not, and may in fact impart protection from oxidant stress. Neither MAPK (i.e., p38, ERK1, ERK2) content nor NF-kappaB activation accounts for the differential sensitivity to oxidant stress among the differentially phosphorylated p75NTR cell lines. However, differences in the time course of ERK1,2 phosphorylation among the lines account in large measure for their differential oxidant sensitivity. The phosphorylation state of specific sites on p75ICD may modulate the resistance of neurons in Alzheimer's disease-relevant brain regions to oxidant stress.
p75 神经生长因子受体（p75NTR）是一种α和γ分泌酶底物，在成年大脑的梅内尔特基底核的胆碱能神经元、海马体和小脑表达更为明显。γ分泌酶、早老素的突变已被牵连到家族性阿尔茨海默病中。此外，对梅内尔特基底核和海马体的胆碱能神经元的氧化和炎症损伤在阿尔茨海默病的病理中起着关键作用。p75NTR 的细胞内域（p75ICD）是全受体的α和γ分泌酶切割片段，在 PC12 大鼠嗜铬细胞瘤细胞中作为抗氧化剂发挥作用。受体的磷酸化被认为是其许多功能所必需的，而 p75ICD 中的两个酪氨酸是功能上重要的磷酸化位点之一。通过定点突变生成了三个分别不能在一个或两个酪氨酸处被磷酸化的 p75ICD 突变体。将每个突变体在 p75NTR 缺陷型 PC12 细胞中表达，以确定在特定位点阻断磷酸化对 p75ICD 的抗氧化活性的影响。干扰酪氨酸-337 的磷酸化会损害抗氧化功能，而干扰酪氨酸-366 的磷酸化则不会，实际上可能提供对氧化应激的保护。MAPK（即 p38、ERK1、ERK2）含量或 NF-κB 激活都不能解释在具有不同磷酸化状态的 p75NTR 细胞系之间对氧化应激的敏感性差异。然而，这些细胞系中 ERK1、2 磷酸化的时间进程差异在很大程度上解释了它们对氧化应激的不同敏感性。p75ICD 上特定位点的磷酸化状态可能调节与阿尔茨海默病相关的大脑区域中神经元对氧化应激的抵抗力。
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