Powerful beneficial effects of macrophage colony-stimulating factor on -amyloid deposition and cognitive impairment in Alzheimers disease
Powerful beneficial effects of macrophage colony-stimulating factor on -amyloid deposition and cognitive impairment in Alzheimers disease
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DOI：
10.1093/brain/awn331
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发表时间：
2009-04-01
期刊：
影响因子：
14.5
通讯作者：
Rivest, Serge
中科院分区：
文献类型：
--
作者：
Boissonneault, Vincent;Filali, Mohammed;Rivest, Serge
阿尔茨海默病是人类痴呆症的主要原因。认知能力下降的出现与一种称为-淀粉样蛋白（A）的短肽的过量产生有关，这种短肽以可溶性和聚集形式存在。在这里，我们表明，注射巨噬细胞集落刺激因子（M-CSF）的瑞典-淀粉样前体蛋白（APP（Swe））/PS1转基因小鼠，一个良好的记录模型阿尔茨海默氏症，每周的基础上出现学习和记忆缺陷预防认知丧失。M-CSF还增加了实质中小胶质细胞的数量，并减少了A沉积物的数量。与溶剂溶液处理的同窝对照组相比，M-CSF处理小鼠脑中的老年斑较小且密度较低。有趣的是，在M-CSF处理的动物的脑中更高比例的小胶质细胞内化A，并且吞噬的肽位于晚期内体和溶酶体中。与溶剂对照相比，在M-CSF处理的转基因小鼠的细胞外蛋白富集组分中也检测到较少的A（40）和A（42）单体。最后，治疗已经表现出安装A病理的APP（Swe）/PS1小鼠稳定了认知能力下降。总之，这些结果提供了令人信服的证据，表明全身M-CSF给药是一种强有力的治疗方法，可刺激骨髓源性小胶质细胞，降解A，并预防或改善阿尔茨海默病小鼠模型中与A负荷相关的认知下降。
Alzheimers disease is a major cause of dementia in humans. The appearance of cognitive decline is linked to the overproduction of a short peptide called -amyloid (A) in both soluble and aggregate forms. Here, we show that injecting macrophage colony-stimulating factor (M-CSF) to Swedish -amyloid precursor protein (APP(Swe))/PS1 transgenic mice, a well-documented model for Alzheimers disease, on a weekly basis prior to the appearance of learning and memory deficits prevented cognitive loss. M-CSF also increased the number of microglia in the parenchyma and decreased the number of A deposits. Senile plaques were smaller and less dense in the brain of M-CSF-treated mice compared to littermate controls treated with vehicle solution. Interestingly, a higher ratio of microglia internalized A in the brain of M-CSF-treated animals and the phagocytosed peptides were located in the late endosomes and lysosomes. Less A(40) and A(42) monomers were also detected in the extracellular protein enriched fractions of M-CSF-treated transgenic mice when compared with vehicle controls. Finally, treating APP(Swe)/PS1 mice that were already demonstrating installed A pathology stabilized the cognitive decline. Together these results provide compelling evidence that systemic M-CSF administration is a powerful treatment to stimulate bone marrow-derived microglia, degrade A and prevent or improve the cognitive decline associated with A burden in a mouse model of Alzheimers disease.