Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Japan.
Am J Pathol. 2009 Nov;175(5):2121-32. doi: 10.2353/ajpath.2009.090418. Epub 2009 Oct 15.
Soluble oligomeric amyloid beta (oAbeta) 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 oAbeta1-42 neurotoxicity is not fully understood. Here, we showed that oAbeta but not fibrillar Abeta was neurotoxic, and microglia activated with unmethylated DNA CpG motif (CpG), a ligand for Toll-like receptor 9, attenuated oAbeta1-42 neurotoxicity in primary neuron-microglia co-cultures. CpG enhanced microglial clearance of oAbeta1-42 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 oAbeta1-42 and the impairment of associative learning in Tg2576 mouse model of AD. We propose that CpG may be an effective therapeutic strategy for limiting oAbeta1-42 neurotoxicity in AD.
可溶性寡聚淀粉样蛋白β（oAbeta）1-42 可引起阿尔茨海默病（AD）中的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 病理学的一个标志，但小胶质细胞在 oAbeta1-42 神经毒性中的作用尚未完全阐明。在这里，我们发现 oAbeta 而不是纤维状 Abeta 具有神经毒性，并且用未甲基化的 DNA CpG 基序（CpG）激活的小胶质细胞，CpG 是 Toll 样受体 9 的配体，可减轻原代神经元-小胶质细胞共培养物中 oAbeta1-42 的神经毒性。CpG 增强了小胶质细胞对 oAbeta1-42 的清除作用，并诱导小胶质细胞中抗氧化酶血红素加氧酶-1 的水平升高，而不会产生神经毒性分子，如一氧化氮和谷氨酸。在 CpG 的亚类中，B 类和 C 类激活小胶质细胞以促进神经保护。此外，脑室内给予 CpG 可改善 oAbeta1-42 诱导的认知障碍以及 AD 转基因小鼠模型中联想学习的损伤。我们提出，CpG 可能是限制 AD 中 oAbeta1-42 神经毒性的有效治疗策略。
