期刊
NEUROCHEMICAL RESEARCH
卷 44, 期 5, 页码 1138-1151出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-019-02748-x
关键词
Alzheimer's disease; Microglia; Systemic inflammation; TLR4; TREM2
资金
- Chongqing Natural Science Foundation [cstc2018jcyjAX0169]
- National Natural Science Foundation of China [81671286, 31570826]
- National Key Clinical Specialties Construction Program of China [[2013]544]
- Chongqing Science & Technology Commission [cstc2014yykfA110002]
Clinically, superimposed systemic inflammation generally has significant deleterious effects on the Alzheimer's disease (AD) progression. However, the related molecular mechanisms remain poorly understood. Microglial toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2) are two key regulators of inflammation that may play an essential role in this complex pathophysiological process. In this study, intraperitoneal injection of lipopolysaccharide (LPS) into APP/PS1 transgenic AD model was used to mimic systemic inflammation in the development of AD. Initial results from the cortex showed that compared with wild-type mice, APP/PS1 mice exhibited elevated gene and protein expression levels of both TLR4 and TREM2 with different degree. Interestingly, after LPS treatment, TLR4 expression was persistently up-regulated, while TREM2 expression was significantly down-regulated in APP/PS1 mice, suggesting that the negative regulatory effect of TREM2 on inflammation might be suppressed by LPS-induced hyperactive TLR4. This imbalance of TLR4/TREM2 contributed to microglial over-activation, followed by increased neuronal apoptosis in the cortex of APP/PS1 mice; these changes did not alter the expression level of A(1-42). Similar alterations were observed in our in vitro experiment with -amyloid(1-42) (A(1-42))-treated N9 microglia. Further, Morris water maze (MWM) testing data indicated that LPS administration acutely aggravated cognitive impairment in APP/PS1 mice, suggesting that the addition of systemic inflammation can potentially accelerate the progression of AD. Collectively, we conclude that an imbalance of TLR4/TREM2 may be a potential link between AD and systemic inflammation. TREM2 can serve as a potential therapeutic target for treating systemic inflammation in AD progression.
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