Amyloid β-Induced Nerve Growth Factor Dysmetabolism in Alzheimer Disease
Amyloid β-Induced Nerve Growth Factor Dysmetabolism in Alzheimer Disease
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DOI：
10.1097/nen.0b013e3181aed9e6
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发表时间：
2009-08-01
影响因子：
3.2
通讯作者：
Cuello, A. Claudio
中科院分区：
文献类型：
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作者：
Bruno, Martin A.;Leon, Wanda C.;Cuello, A. Claudio
我们之前报道过，神经生长因子前体（pro-NGF）和未成熟的 NGF 在中枢神经系统中以所有活动依赖性方式释放，并且其成熟和降解通过蛋白酶的协调作用在细胞外空间发生。在这里，我们提出的证据表明，与对照组相比，阿尔茨海默病 (AD) 大脑样本中 proNGF 向成熟细胞的转化减少，并且 NGF 降解更大。 NGF 代谢途径的这些改变可能导致 proNGF 水平升高。 AD 样品中的 pro-NGF 大部分呈过氧亚硝酸盐形式。海马内注射β-淀粉样蛋白寡聚物引起了幼稚大鼠中类似的pro-NGF上调，并伴有小胶质细胞活化（CD40）的证据，诱导型一氧化氮合酶水平增加，以及NGF降解酶基质金属蛋白酶9活性增加。诱导型一氧化氮合酶升高引发了一代 在注射淀粉样蛋白-β寡聚体的大鼠中，观察生物无活性、过亚硝酸盐修饰的 NGF 前体的变化。这些参数通过米诺环素治疗得到纠正。米诺环素还可以减少改变的基质金属蛋白酶 9、诱导型一氧化氮合酶和小胶质细胞活化 (CD40)；改善认知行为；转基因小鼠 AD 模型中的 pro-NGF 水平标准化。淀粉样蛋白-β淀粉样蛋白中枢神经系统负担NGF代谢的作用可以解释AD中前脑胆碱能神经元萎缩的前NGF矛盾上调。
We previously reported that the precussor form of nerve growth factor (pro-NGF) and not mature NGF is liberated in the CNS ill all activity-dependent manner, and that its maturation and degradation occur in the extracellur space by the coordinated action of proteases. Here, we present evidence of diminished conversion of proNGF to itsmature from and of greater NGF degradation in Alzheimer disease (AD) brain samples compared with controls. These alterations of the NGF metabolic pathway likely resulted in the increased proNGF levels. The pro-NGF was largely in a peroxynitrited form in the AD samples. Intrahippocampal injection of amyloid-beta oligomers provoked similar upregulation of pro-NGF in naive rats that was accompanied by evidence of microglial activation (CD40), increased levels of inducible nitric oxide synthase, and increased activity of the NGF-degrading enzyme matrix metalloproteinase 9. The elevated inducible nitric oxide synthase provoked the generation of biologically inactive, peroxynitrite-modified pro-NGF in amyloid-beta oligomer-injected rats. These parameters were corrected by minocycline treatment. Minocycline also diminished altered matrix metalloproteinase 9, inducible nitric oxide synthase, and microglial activation (CD40); improved cognitive behavior; and normalized pro-NGF levels ill a transgenic mouse AD model. The effects of amyloid-beta amyloid CNS burden oil NGF metabolism may explain the paradoxical upregulation of pro-NGF in AD accompanied by atrophy of forebrain cholinergic neurons.