CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis.
CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis.
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DOI：
10.1523/jneurosci.4403-10.2010
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发表时间：
2010-12-15
期刊：
影响因子：
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通讯作者：
Grutzendler J
中科院分区：
文献类型：
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作者：
Liu Z;Condello C;Schain A;Harb R;Grutzendler J
在阿尔茨海默病（AD）中，淀粉样蛋白-β（Aβ）沉积物经常被活化的小胶质细胞包围，但这些细胞在疾病进展中的确切作用仍不清楚。趋化因子受体CX 3CR 1在小胶质细胞中选择性表达，并被认为调节其活性。为了研究小胶质细胞激活对体内淀粉样蛋白病理学的具体影响，我们将缺乏CX 3CR 1的小鼠与阿尔茨海默病小鼠模型CRND 8杂交。令人惊讶的是，我们发现CX 3CR 1缺陷小鼠的Aβ40和Aβ42脑水平较低，淀粉样蛋白沉积减少。对小胶质细胞内Aβ的定量和对活小鼠进行的延时双光子显微镜检查显示，这些细胞在摄取原纤维淀粉样蛋白方面非常有效，但不能吞噬纤维状嗜酸性Aβ。CX 3CR 1缺失与吞噬能力增加相关，导致小胶质细胞吞噬溶酶体内淀粉样蛋白含量增加。此外，CX 3CR 1缺陷小鼠由于较高的增殖率，单个斑块周围的小胶质细胞数量增加，这可能有助于整体更大的吞噬能力。尽管小胶质细胞密度增加，CX 3CR 1缺失并不影响斑块周围神经元或突触损伤的程度。我们的研究结果表明，小胶质细胞可以通过选择性的原纤维Aβ吞噬作用调节脑Aβ水平和斑块沉积。通过CX 3CR 1信号调节小胶质细胞活性和增殖可能代表AD的治疗策略。
In Alzheimer’s disease (AD), amyloid-β (Aβ) deposits are frequently surrounded by activated microglia but the precise role of these cells in disease progression remains unclear. The chemokine receptor CX3CR1 is selectively expressed in microglia and is thought to modulate their activity. To study the specific effects of microglia activation on amyloid pathology in vivo, we crossbred mice lacking CX3CR1 with the Alzheimer’s mouse model CRND8. Surprisingly, we found that CX3CR1 deficient mice had lower brain levels of Aβ40 and Aβ42 and reduced amyloid deposits. Quantification of Aβ within microglia and time-lapse two photon microscopy in live mice revealed that these cells were highly effective at the uptake of protofibrillar amyloid but were incapable of phagocytosis of fibrillar congophilic Aβ. CX3CR1 deletion was associated with increased phagocytic ability which led to greater amyloid content within microglial phagolysosomes. Furthermore, CX3CR1 deficient mice had an increased number of microglia around individual plaques due to higher proliferative rates, which likely contributed to an overall greater phagocytic capacity. CX3CR1 deletion did not affect the degree of neuronal or synaptic damage around plaques despite increased microglia density. Our results demonstrate that microglia can regulate brain Aβ levels and plaque deposition via selective protofibrillar Aβ phagocytosis. Modulation of microglia activity and proliferation by CX3CR1 signaling may represent a therapeutic strategy for AD.