Hematopoietic CC-Chemokine Receptor 2 (CCR2) Competent Cells Are Protective for the Cognitive Impairments and Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease
Hematopoietic CC-Chemokine Receptor 2 (CCR2) Competent Cells Are Protective for the Cognitive Impairments and Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease
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DOI：
10.2119/molmed.2011.00306
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发表时间：
2012-02-01
影响因子：
5.7
通讯作者：
Rivest, Serge
中科院分区：
文献类型：
--
作者：
Naert, Gaelle;Rivest, Serge
在阿尔茨海默病（AD）小鼠模型中，单核细胞从骨髓中迁移，可向脑内浸润，分化为小胶质细胞，清除脑内淀粉样蛋白β（A β）。在这里，我们表明，这些机制特别需要CC-趋化因子受体2（CCR 2）在骨髓细胞（BMC）的表达。在携带CCR 2缺陷型BMC的APP（Swe）/PS1小鼠（表达嵌合淀粉样前体蛋白（APPSwe）和人早老素1（PS1）的转基因小鼠）中，疾病进展加剧。事实上，移植CCR 2缺陷的BMCs增强了记忆缺陷，并增加了可溶性A β的量和转化生长因子（TGF）-β 1和TGF-β受体的表达。相比之下，移植野生型骨髓干细胞恢复了APP（Swe）/PS1和APP（Swe）/PS1/CCR 2（-/-）小鼠的记忆能力，并减少了可溶性A β的积累。最后，在骨髓基质细胞中使用慢病毒表达CCR 2转基因的基因治疗可以预防AD小鼠模型的认知能力下降。注射CCR 2慢病毒恢复了单核细胞中CCR 2的表达和功能。这些细胞存在于非辐照的APP（Swe）/PS1/CCR 2（-/-）小鼠的脑中支持了它们可用作AD的基因载体的概念。因此，骨髓来源的小胶质细胞中CCR 2表达降低可能在这种神经退行性疾病的病因学中起主要作用。在线地址：http://www.molmed.org doi：10.2119/molmed.2011.00306
Monocytes emigrate from bone marrow, can infiltrate into brain, differentiate into microglia and clear amyloid beta (A beta) from the brain of mouse models of Alzheimer's disease (AD). Here we show that these mechanisms specifically require CC-chemokine receptor 2 (CCR2) expression in bone marrow cells (BMCs). Disease progression was exacerbated in APP(Swe)/PS1 mice (transgenic mice expressing a chimeric amyloid precursor protein (APPSwe) and human presenilin 1 (PS1)) harboring CCR2-deficient BMCs. Indeed, transplantation of CCR2-deficient BMCs enhanced the mnesic deficit and increased the amount of soluble A beta and expression of transforming growth factor (TGF)-beta 1 and TGF-beta receptors. By contrast, transplantation of wild-type bone marrow stem cells restored memory capacities and diminished soluble A beta accumulation in APP(Swe)/PS1 and APP(Swe)/PS1/CCR2(-/-) mice. Finally, gene therapy using a lentivirus-expressing CCR2 transgene in BMCs prevented cognitive decline in this mouse model of AD. Injection of CCR2 lentiviruses restored CCR2 expression and functions in monocytes. The presence of these cells in the brain of non-irradiated APP(Swe)/PS1/CCR2(-/-) mice supports the concept that they can be used as gene vehicles for AD. Decreased CCR2 expression in bone marrow-derived microglia may therefore play a major role in the etiology of this neurodegenerative disease. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00306