Stahl Tobias, Reimers Christine, Johne Reimar, Schliebs Reinhard, Seeger Johannes
Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 43, D-04109 Leipzig, Germany.
Eur J Neurosci. 2006 Oct;24(7):1923-34. doi: 10.1111/j.1460-9568.2006.05069.x.
Amyloid plaques, one of the neuropathological hallmarks of Alzheimer's disease, and their main constituent, the amyloid beta-peptide (Abeta), are triggers of the activation of innate inflammatory mechanisms involving the activation of microglia. To dissect the effects of a non-Abeta-specific microglial activation on the Abeta metabolism, we employed a viral infection-based model. Transgenic mice expressing a mutated form of the human amyloid precursor protein (Tg2576) were used. In preceding experiments, 2-week-old transgenic mice and non-transgenic littermates were infected intracerebrally with the neurotropic Borna disease virus and investigated at 2, 4 and 14 weeks post-infection. The Borna disease virus-inoculated mice showed a persisting, subclinical infection of cortical and limbic brain areas characterized by slight T-cell infiltrates, expression of cytokines and a massive microglial activation in the hippocampus and neocortex. Viral-induced effects reached their peak at 4 weeks post-infection. In 14-month-old Tg2576 mice, characterized by the deposition of diffuse and dense-core amyloid plaques in cortical brain regions, Borna disease virus-induced microglial activation in the vicinity of Abeta deposits was used to investigate the influence of a local inflammatory response on these deposits. At 4 weeks post-infection, histometric analyses employing Abeta immunohistochemistry revealed a decrease of the cortical and hippocampal Abeta-immunopositive area. This overall decrease was accompanied by a decrease of parenchymal thioflavin-S-positive amyloid deposits and an increase of such deposits in the walls of cerebral vessels, which indicates that the elicitation of a non-Abeta-specific microglial activation may contribute to a reduction of Abeta in the brain parenchyma.
淀粉样斑块是阿尔茨海默病的神经病理学特征之一，其主要成分淀粉样β肽（Aβ）是激活涉及小胶质细胞激活的先天性炎症机制的触发因素。为了剖析非Aβ特异性小胶质细胞激活对Aβ代谢的影响，我们采用了基于病毒感染的模型。使用了表达人类淀粉样前体蛋白突变形式的转基因小鼠（Tg2576）。在之前的实验中，2周龄的转基因小鼠和同窝非转基因小鼠脑内接种嗜神经性博尔纳病病毒，并在感染后2周、4周和14周进行研究。接种博尔纳病病毒的小鼠表现出皮质和边缘脑区持续的亚临床感染，其特征为轻微的T细胞浸润、细胞因子表达以及海马体和新皮质中大量的小胶质细胞激活。病毒诱导的效应在感染后4周达到峰值。在14月龄的Tg2576小鼠中，其皮质脑区有弥漫性和致密核心淀粉样斑块沉积，利用博尔纳病病毒诱导Aβ沉积物附近的小胶质细胞激活来研究局部炎症反应对这些沉积物的影响。感染后4周，采用Aβ免疫组织化学的组织计量学分析显示皮质和海马体中Aβ免疫阳性区域减少。这种总体减少伴随着实质硫黄素-S阳性淀粉样沉积物的减少以及脑血管壁中此类沉积物的增加，这表明非Aβ特异性小胶质细胞激活的引发可能有助于减少脑实质中的Aβ。
