Mattson M P, Barger S W, Furukawa K, Bruce A J, Wyss-Coray T, Mark R J, Mucke L
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Brain Res Brain Res Rev. 1997 Feb;23(1-2):47-61. doi: 10.1016/s0165-0173(96)00014-8.
beta-Amyloid precursor protein (beta APP), transforming growth factor beta (TGF beta), and tumor necrosis factor-alpha (TNF alpha) are remarkably pleiotropic neural cytokines/neurotrophic factors that orchestrate intricate injury-related cellular and molecular interactions. The links between these three factors include: their responses to injury; their interactive effects on astrocytes, microglia and neurons; their ability to induce cytoprotective responses in neurons; and their association with cytopathological alterations in Alzheimer's disease. Astrocytes and microglia each produce and respond to TGF beta and TNF alpha in characteristic ways when the brain is injured. TGF beta, TNF alpha and secreted forms of beta APP (sAPP) can protect neurons against excitotoxic, metabolic and oxidative insults and may thereby serve neuroprotective roles. On the other hand, under certain conditions TNF alpha and the fibrillogenic amyloid beta-peptide (A beta) derivative of beta APP can promote damage of neuronal and glial cells, and may play roles in neurodegenerative disorders. Studies of genetically manipulated mice in which TGF beta, TNF alpha or beta APP ligand or receptor levels are altered suggest important roles for each factor in cellular responses to brain injury and indicate that mediators of neural injury responses also have the potential to enhance amyloidogenesis and/or to interfere with neuroregeneration if expressed at abnormal levels or modified by strategic point mutations. Recent studies have elucidated signal transduction pathways of TGF beta (serine/threonine kinase cascades), TNF alpha (p55 receptor linked to a sphingomyelin-ceramide-NF kappa B pathway), and secreted forms of beta APP (sAPP; receptor guanylate cyclase-cGMP-cGMP-dependent kinase-K+ channel activation). Knowledge of these signaling pathways is revealing novel molecular targets on which to focus neuroprotective therapeutic strategies in disorders ranging from stroke to Alzheimer's disease.
β-淀粉样前体蛋白（βAPP）、转化生长因子β（TGFβ）和肿瘤坏死因子-α（TNFα）是具有显著多效性的神经细胞因子/神经营养因子，它们协调复杂的损伤相关细胞和分子相互作用。这三种因子之间的联系包括：它们对损伤的反应；它们对星形胶质细胞、小胶质细胞和神经元的相互作用效应；它们在神经元中诱导细胞保护反应的能力；以及它们与阿尔茨海默病细胞病理学改变的关联。当大脑受到损伤时，星形胶质细胞和小胶质细胞各自以独特的方式产生并对TGFβ和TNFα作出反应。TGFβ、TNFα和βAPP的分泌形式（sAPP）可以保护神经元免受兴奋性毒性、代谢和氧化损伤，从而可能发挥神经保护作用。另一方面，在某些条件下，TNFα和βAPP的纤维原性淀粉样β肽（Aβ）衍生物可促进神经元和神经胶质细胞的损伤，并可能在神经退行性疾病中起作用。对TGFβ、TNFα或βAPP配体或受体水平发生改变的基因操作小鼠的研究表明，每种因子在细胞对脑损伤的反应中都起着重要作用，并表明如果神经损伤反应的介质以异常水平表达或通过定点突变进行修饰，它们也有可能增强淀粉样蛋白生成和/或干扰神经再生。最近的研究阐明了TGFβ（丝氨酸/苏氨酸激酶级联反应）、TNFα（与鞘磷脂-神经酰胺-NFκB途径相连的p55受体）和βAPP分泌形式（sAPP；受体鸟苷酸环化酶-cGMP-cGMP依赖性激酶-K+通道激活）的信号转导途径。对这些信号转导途径的了解正在揭示新的分子靶点，可将神经保护治疗策略聚焦于从中风到阿尔茨海默病等各种疾病。
