Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand.
Neuroscience. 2011 Oct 13;193:269-82. doi: 10.1016/j.neuroscience.2011.07.054. Epub 2011 Jul 27.
Amyloid beta (Aβ) has been proposed to play a central and causative role in the development of Alzheimer's disease. Aβ(25-35), the neurotoxic domain of the full-length Aβ, causes learning and memory impairments in rodents. The present study investigated the effects of a single bilateral i.c.v. infusion of pre-aggregated Aβ(25-35) (30 nmol/rat) on animals' performance in the open field, and on arginine metabolic enzymes and metabolites in the CA1, CA2/3, and dentate gyrus (DG) sub-regions of the hippocampus and prefrontal cortex (PFC) at the time point of 6-8 days after Aβ infusion. Aβ(25-35) rats displayed reduced exploratory activity in the open field relative to the Aβ(35-25) (reverse peptide; 30 nmol) rats. Aβ(25-35) resulted in significantly decreased nitric oxide synthase (NOS) activity and endothelial NOS protein expression, but increased arginase activity, arginase II protein expression, and ornithine and putrescine levels, in hippocampal CA2/3. There were increased glutamate and putrescine levels in the DG, but decreased agmatine levels in the DG and PFC, in the Aβ(25-35) group relative to the Aβ(35-25) one. Cluster analyses were performed to determine if the nine related neurochemical variables (arginine, citrulline, ornithine, agmatine, putrescine, spermidine, spemine, glutamate, and GABA) formed distinct groups, and whether it changed as a function of Aβ(25-35). There were substantially different clusters between the two groups in the hippocampus and PFC. These results demonstrate that Aβ(25-35) alters arginine metabolism, which further supports the prominent role of arginine and its metabolites in Alzheimer's disease (AD) pathogenesis.
淀粉样蛋白β（Aβ）被认为在阿尔茨海默病的发展中起核心和因果作用。全长 Aβ的神经毒性结构域 Aβ（25-35）在啮齿动物中引起学习和记忆障碍。本研究探讨了单次双侧脑室内（i.c.v.）输注预聚集的 Aβ（25-35）（30 nmol/大鼠）对动物在旷场中的表现的影响，以及在 Aβ 输注后 6-8 天对海马 CA1、CA2/3 和齿状回（DG）亚区以及前额叶皮层（PFC）中的精氨酸代谢酶和代谢物的影响。与 Aβ（35-25）（反向肽；30 nmol）大鼠相比，Aβ（25-35）大鼠在旷场中表现出减少的探索活动。Aβ（25-35）导致海马 CA2/3 中的一氧化氮合酶（NOS）活性和内皮型 NOS 蛋白表达显著降低，但精氨酸酶活性、精氨酸酶 II 蛋白表达以及鸟氨酸和腐胺水平增加。DG 中的谷氨酸和腐胺水平增加，但 DG 和 PFC 中的胍丁胺水平降低，与 Aβ（25-35）组相比。聚类分析用于确定九个相关神经化学变量（精氨酸、瓜氨酸、鸟氨酸、胍丁胺、腐胺、亚精胺、精胺、谷氨酸和 GABA）是否形成不同的组，以及它们是否随 Aβ（25-35）的变化而变化。两组在海马体和 PFC 之间有明显不同的聚类。这些结果表明 Aβ（25-35）改变了精氨酸代谢，这进一步支持了精氨酸及其代谢物在阿尔茨海默病（AD）发病机制中的突出作用。
