Microglia Play an Active Role in Obesity-Associated Cognitive Decline
Microglia Play an Active Role in Obesity-Associated Cognitive Decline
复制标题
DOI：
10.1523/jneurosci.0789-18.2018
复制
发表时间：
2018-10-10
影响因子：
5.3
通讯作者：
Gould, Elizabeth
中科院分区：
文献类型：
--
作者：
Cope, Elise C.;LaMarca, Elizabeth A.;Gould, Elizabeth
肥胖影响着全世界超过6亿人，这是一个似乎正在上升的惊人数字。肥胖的一个鲜为人知的后果是它对认知的有害影响，这在许多认知领域和年龄组中都有很好的记录。为了研究与肥胖相关的认知能力下降的细胞机制，我们在雄性小鼠中使用饮食诱导的肥胖，发现记忆障碍伴随着树突棘（兴奋性突触的部位）的减少、小胶质细胞（大脑的常驻免疫细胞）的激活增加以及海马体（与认知相关的大脑区域）中小胶质细胞内突触分布的增加沿着。我们发现，部分敲除fractalkine受体（一种可以作为小胶质细胞“找到我”线索的趋化因子），可以防止肥胖引起的小胶质细胞活化和认知能力下降。此外，我们发现肥胖小鼠中小胶质细胞活化的药理学抑制与树突棘丢失和认知退化的预防有关。最后，我们观察到药物阻断小胶质细胞吞噬作用可减轻肥胖相关的认知能力下降。这些发现表明，小胶质细胞通过吞噬对最佳功能至关重要的突触，在肥胖相关的认知功能下降中发挥积极作用。
Obesity affects >600 million people worldwide, a staggering number that appears to be on the rise. One of the lesser known consequences of obesity is its deleterious effects on cognition, which have been well documented across many cognitive domains and age groups. To investigate the cellular mechanisms that underlie obesity-associated cognitive decline, we used diet-induced obesity in male mice and found memory impairments along with reductions in dendritic spines, sites of excitatory synapses, increases in the activation of microglia, the brain's resident immune cells, and increases in synaptic profiles within microglia, in the hippocampus, a brain region linked to cognition. We found that partial knockdown of the receptor for fractalkine, a chemokine that can serve as a "find me" cue for microglia, prevented microglial activation and cognitive decline induced by obesity. Furthermore, we found that pharmacological inhibition of microglial activation in obese mice was associated with prevention of both dendritic spine loss and cognitive degradation. Finally, we observed that pharmacological blockade of microglial phagocytosis lessened obesity-associated cognitive decline. These findings suggest that microglia play an active role in obesity-associated cognitive decline by phagocytosis of synapses that are important for optimal function.