Microglia Activated with the Toll-Like Receptor 9 Ligand CpG Attenuate Oligomeric Amyloid β Neurotoxicity in in Vitro and in Vivo Models of Alzheimer's Disease
Microglia Activated with the Toll-Like Receptor 9 Ligand CpG Attenuate Oligomeric Amyloid β Neurotoxicity in in Vitro and in Vivo Models of Alzheimer's Disease
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DOI：
10.2353/ajpath.2009.090418
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发表时间：
2009-11-01
影响因子：
6
通讯作者：
Suzumura, Akio
中科院分区：
文献类型：
--
作者：
Doi, Yukiko;Mizuno, Tetsuya;Suzumura, Akio
可溶性寡聚淀粉样蛋白β（oA β）1-42在阿尔茨海默病（AD）中引起突触功能障碍和神经元损伤。虽然小胶质细胞在老年斑周围的积累是AD病理学的标志，但小胶质细胞在oA β 1-42神经毒性中的作用尚未完全了解。在这里，我们发现oA β而不是纤维状A β是神经毒性的，并且在原代神经元-小胶质细胞共培养物中，用Toll样受体9的配体非甲基化DNA CpG基序（CpG）激活的小胶质细胞减弱了oA β 1-42的神经毒性。CpG增强了小胶质细胞对oA β 1-42的清除，并诱导小胶质细胞中抗氧化酶血红素加氧酶-1水平升高，而不产生神经毒性分子，如一氧化氮和谷氨酸。在CpG亚类中，B类和C类活化小胶质细胞以促进神经保护。此外，脑室内施用CpG改善了由oA β 1-42诱导的认知障碍和AD的Tg 2576小鼠模型中的联合学习障碍。我们认为CpG可能是限制AD中oA β 1-42神经毒性的有效治疗策略。(Am J Pathol 2009，175：2121-2132; DOI：10.2353/ajpath.2009.090418）
Soluble oligomeric amyloid beta (oA beta) 1-42 causes synaptic dysfunction and neuronal injury in Alzheimer's disease (AD). Although accumulation of microglia around senile plaques is a hallmark of AD pathology, the role of microglia in oA beta 1-42 neurotoxicity is not fully understood. Here, we showed that oA beta but not fibrillar A beta was neurotoxic, and microglia activated with unmethylated DNA CpG motif (CpG), a ligand for Toll-like receptor 9, attenuated oA beta 1-42 neurotoxicity in primary neuron-microglia co-cultures. CpG enhanced microglial clearance of oA beta 1-42 and induced higher levels of the antioxidant enzyme heme oxygenase-1 in microglia without producing neurotoxic molecules such as nitric oxide and glutamate. Among subclasses of CpGs, class B and class C activated microglia to promote neuroprotection. Moreover, intracerebroventricular administration of CpG ameliorated both the cognitive impairments induced by oA beta 1-42 and the impairment of associative learning in Tg2576 mouse model of AD. We propose that CpG may he an effective therapeutic strategy for limiting oA beta 1-42 neurotoxicity in AD. (Am J Pathol 2009, 175:2121-2132; DOI: 10.2353/ajpath.2009.090418)