低度全身炎症刺激小胶质细胞更新并加速阿尔茨海默病样病理的发生

Low-grade systemic inflammation stimulates microglial turnover and accelerates the onset of Alzheimer's-like pathology

数项在体研究表明,脂多糖模拟的全身炎症会引发中枢神经系统中由小胶质细胞驱动的炎症反应,其特征是炎症细胞因子和相关疾病行为的增加。然而,大多数研究诱发相对较高的全身炎症,并没有直接与人类在生命过程中经历的更常见的低度炎症事件进行比较。本研究利用小鼠研究低度全身炎症在生命早期对健康的影响,以及该事件如何影响阿尔茨海默病(AD)样病理的发生和严重程度。本研究结果表明,低度全身炎症会诱导阈下脑炎症,并促进CSF1R通路驱动的小胶质细胞增殖,这与高度全身炎症引起的影响相反。此外,低度脂多糖引起的反复全身性挑战会诱导疾病相关的小胶质细胞。最后,使用AD样病理诱导模型(102系小鼠),我们观察到在APP诱导之前重复剂量的低度全身性炎症预处理会在以后的生活中产生有害影响,导致Aβ沉积以及和疾病相关的小胶质细胞增加。本研究结果提示,阵发性低度全身炎症有可能影响与年龄相关的神经系统疾病(例如AD)的发作和严重程度。

Several in vivo studies have shown that systemic inflammation,mimicked by LPS,triggers an inflamma-tory response in the CNS,driven by microglia,characterized by an increase in inflammatory cytokines and associat-ed sickness behavior.However,most studies induce relatively high systemic inflammation,not directly compared with the more common low-grade inflammatory events experienced in humans during the life course.Using mice,we investigated the effects of low-grade systemic inflammation during an otherwise healthy early life,and how this may precondition the onset and severity of Alzheimer's disease(AD)-like pathology.Our results indicate that low-grade systemic inflammation induces sub-threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway,contrary to the effects caused by high systemic inflammation.In addition,repeated systemic challenges with low-grade LPS induce disease-associated microglia.Finally,using an inducible model of AD-like pathology(Line 102 mice),we observed that preconditioning with repeated doses of low-grade systemic in-flammation,prior to APP induction,promotes a detrimental effect later in life,leading to an increase in Aβaccumula-tion and disease-associated microglia.These results support the notion that episodic low-grade systemic inflamma-tion has the potential to influence the onset and severity of age-related neurological disorders,such as AD.