Lipolysaccharide-Induced Neuroinflammation Is Associated with Alzheimer-Like Amyloidogenic Axonal Pathology and Dendritic Degeneration in Rats.

Xiaohua Deng, Meili Li, Weiming Ai, Lixin He, Dahua Lu, Peter R Patrylo, Huaibin Cai, Xuegang Luo, Zhiyuan Li, Xiaoxin Yan
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Abstract

Chronic neuroinflammation is thought to play an etiological role in Alzheimer's disease (AD), which is characterized pathologically by amyloid and tau formation, as well as neuritic dystrophy and synaptic degeneration. The causal relationship between these pathological events is a topic of ongoing research and discussion. Recent data from transgenic AD models point to a tight spatiotemporal link between neuritic and amyloid pathology, with the obligatory enzyme for β-amyloid (Aβ) production, namely β-secretase-1 (BACE1), is overexpressed in axon terminals undergoing dystrophic change. However, the axonal pathology inherent with BACE1 elevation seen in transgenic AD mice may be secondary to increased soluble Aβ in these genetically modified animals. Here we explored the occurrence of the AD-like axonal and dendritic pathology in adult rat brain affected by LPS-induced chronic neuroinflammation. Unilateral intracerebral LPS injection induced prominent inflammatory response in glial cells in the ipsilateral cortex and hippocampal formation. BACE1 protein levels were elevated the ipsilateral hippocampal lysates in the LPS treated animals relative to controls. BACE1 immunoreactive dystrophic axons appeared in the LPS-treated ipsilateral cortex and hippocampal formation, colocalizing with increased β-amyloid precursor protein and Aβ antibody (4G8) immunolabeling. Quantitative Golgi studies revealed reduction of dendritic branching points and spine density on cortical layer III and hippocampal CA3 pyramidal neurons in the LPS-treated ipsilateral cerebrum. These findings suggest that Alzheimer-like amyloidogenic axonal pathology and dendritic degeneration occur in wildtype mammalian brain in partnership with neuroinflammation following LPS injection.

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脂多糖诱导的神经炎症与大鼠阿尔茨海默样淀粉样轴突病理和树突状变性有关。
慢性神经炎症被认为在阿尔茨海默病(AD)中起病因学作用,阿尔茨海默病的病理特征是淀粉样蛋白和tau蛋白的形成,以及神经性营养不良和突触变性。这些病理事件之间的因果关系是一个正在进行的研究和讨论的主题。来自转基因AD模型的最新数据表明,神经炎和淀粉样蛋白病理之间存在紧密的时空联系,β-淀粉样蛋白(a β)产生的必需酶β-分泌酶-1 (BACE1)在发生营养不良变化的轴突末端过度表达。然而,在转基因AD小鼠中,BACE1升高所固有的轴突病理可能继发于这些转基因动物中可溶性Aβ的增加。本研究探讨lps诱导的慢性神经炎症对成年大鼠脑ad样轴突和树突病理的影响。单侧脑内注射LPS诱导同侧皮质和海马形成的胶质细胞出现明显的炎症反应。与对照组相比,LPS处理动物同侧海马裂解物中BACE1蛋白水平升高。在lps处理的同侧皮质和海马形成中出现BACE1免疫反应性营养不良轴突,共定位增加β-淀粉样蛋白前体蛋白和Aβ抗体(4G8)免疫标记。定量高尔基体研究显示,lps处理的同侧大脑皮层III层和海马CA3锥体神经元的树突分支点和脊柱密度减少。这些发现表明,在LPS注射后,野生型哺乳动物大脑中发生阿尔茨海默样淀粉样样轴突病理和树突状变性,并伴有神经炎症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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