Rogers Justin T, Liu Chia-Chen, Zhao Na, Wang Jian, Putzke Travis, Yang Longyu, Shinohara Mitsuru, Fryer John D, Kanekiyo Takahisa, Bu Guojun
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China.
Neurobiol Aging. 2017 May;53:112-121. doi: 10.1016/j.neurobiolaging.2017.02.001. Epub 2017 Feb 9.
Aging is accompanied by increased neuroinflammation, synaptic dysfunction, and cognitive deficits both in rodents and humans, yet the onset and progression of these deficits throughout the life span remain unknown. These aging-related deficits affect the quality of life and present challenges to our aging society. Here, we defined age-dependent and progressive impairments of synaptic and cognitive functions and showed that reducing astrocyte-related neuroinflammation through anti-inflammatory drug treatment in aged mice reverses these events. By comparing young (3 months), middle-aged (18 months), aged (24 months), and advanced-aged wild-type mice (30 months), we found that the levels of an astrocytic marker, glial fibrillary acidic protein, progressively increased after 18 months of age, which preceded the decreases of the synaptic marker PSD-95. Hippocampal long-term potentiation was also suppressed in an age-dependent manner, where significant deficits were observed after 24 months of age. Fear conditioning tests demonstrated that associative memory in the context and cued conditions was decreased starting at the ages of 18 and 30 months, respectively. When the mice were tested on hidden platform water maze, spatial learning memory was significantly impaired after 24 months of age. Importantly, subacute treatment with the anti-inflammatory drug ibuprofen suppressed astrocyte activation and restored synaptic plasticity and memory function in advanced-aged mice. These results support the critical contribution of aging-related inflammatory responses to hippocampal-dependent cognitive function and synaptic plasticity, in particular during advanced aging. Our findings provide strong evidence that suppression of neuroinflammation could be a promising treatment strategy to preserve cognition during aging.
衰老伴随着神经炎症增加、突触功能障碍和认知缺陷，在啮齿动物和人类中均是如此，但这些缺陷在整个生命周期中的发生和进展仍不清楚。这些与衰老相关的缺陷影响生活质量，并给我们的老龄化社会带来挑战。在这里，我们定义了突触和认知功能的年龄依赖性和渐进性损伤，并表明通过对老年小鼠进行抗炎药物治疗来减少与星形胶质细胞相关的神经炎症可逆转这些情况。通过比较年轻（3个月）、中年（18个月）、老年（24个月）和高龄野生型小鼠（30个月），我们发现星形胶质细胞标志物胶质纤维酸性蛋白的水平在18个月龄后逐渐升高，这早于突触标志物PSD-95的下降。海马体长期增强效应也以年龄依赖性方式受到抑制，在24个月龄后观察到明显缺陷。恐惧条件测试表明，在情境和线索条件下的联想记忆分别在18个月和30个月龄时开始下降。当在隐藏平台水迷宫中对小鼠进行测试时，空间学习记忆在24个月龄后显著受损。重要的是，用抗炎药物布洛芬进行亚急性治疗可抑制星形胶质细胞激活，并恢复高龄小鼠的突触可塑性和记忆功能。这些结果支持了与衰老相关的炎症反应对海马体依赖性认知功能和突触可塑性的关键作用，特别是在高龄期。我们的研究结果提供了强有力证据，表明抑制神经炎症可能是在衰老过程中保持认知的一种有前景的治疗策略。
