GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice.
GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice.
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DOI：
10.3233/jad-2010-091471
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Potter H
中科院分区：
文献类型：
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作者：
Boyd TD;Bennett SP;Mori T;Governatori N;Runfeldt M;Norden M;Padmanabhan J;Neame P;Wefes I;Sanchez-Ramos J;Arendash GW;Potter H
类风湿性关节炎（RA）是阿尔茨海默病（AD）发展的负风险因素。虽然通常认为RA患者使用非甾体抗炎药（NSAID）有助于预防AD的发作和进展，但NSAID临床试验已证明在AD患者中不成功。为了确定是否内在因素在RA发病机制本身可能是RA的保护作用的基础，我们研究了活性的集落刺激因子，上调RA，对转基因AD小鼠的病理和行为。将5 μg巨噬细胞、粒细胞和粒细胞-巨噬细胞集落刺激因子（M-CSF、G-CSF或GM-CSF）单方面推注到老年认知受损AD小鼠的海马体中，并在一周后测定由此产生的淀粉样蛋白负荷降低，使用人工脑脊液注射的对侧作为对照。更重要的是，在向AD小鼠推注给药后一周，GM-CSF减少了整个治疗的脑半球的淀粉样变性。在一系列认知测试中评估后，向AD小鼠的平衡队列给予20次每日皮下注射5 μg GM-CSF（推注实验中淀粉样蛋白减少最多的CSF）。评估淀粉样蛋白负荷的减少和认知功能的改善。皮下注射GM-CSF显著减少脑淀粉样变性，完全逆转认知障碍，同时增加海马突触面积和小胶质细胞密度。这些发现，沿着在老年白细胞减少症患者中使用Leukine（重组人GM-CSF）的二十年累积安全性数据，表明应将Leukine作为逆转AD中脑淀粉样蛋白病理学和认知障碍的治疗进行试验。
Rheumatoid arthritis (RA) is a negative risk factor for the development of Alzheimer’s disease (AD). While it has been commonly assumed that RA patients’ usage of non-steroidal anti-inflammatory drugs (NSAIDs) helped prevent onset and progression of AD, NSAID clinical trials have proven unsuccessful in AD patients. To determine whether intrinsic factors within RA pathogenesis itself may underlie RA’s protective effect, we investigated the activity of colony-stimulating factors, upregulated in RA, on the pathology and behavior of transgenic AD mice. 5 µg bolus injections of macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factors (M-CSF, G-CSF, or GM-CSF) were administered unilaterally into the hippocampus of aged cognitively-impaired AD mice and the resulting amyloid load reductions determined one week later, using the artificial cerebrospinal fluid-injected contralateral sides as controls. G-CSF and more significantly, GM-CSF reduced amyloidosis throughout the treated brain hemisphere one week following bolus administration to AD mice. 20 daily subcutaneous injections of 5 µg of GM-CSF (the most amyloid-reducing CSF in the bolus experiment) were administered to balanced cohorts of AD mice after assessment in a battery of cognitive tests. Reductions in amyloid load and improvements in cognitive function were assessed. Subcutaneous GM-CSF administration significantly reduced brain amyloidosis and completely reversed the cognitive impairment, while increasing hippocampal synaptic area and microglial density. These findings, along with two decades of accrued safety data using Leukine, recombinant human GM-CSF, in elderly leukopenic patients, suggest that Leukine should be tested as a treatment to reverse cerebral amyloid pathology and cognitive impairment in AD.