Imbalance of Microglial TLR4/TREM2 in LPS-Treated APP/PS1 Transgenic Mice: A Potential Link Between Alzheimer’s Disease and Systemic Inflammation

Feb 14, 2019Neurochemical research

Imbalance of Brain Immune Sensors in Mice with Alzheimer's Genes After Inflammation: A Possible Link Between Alzheimer's and Body-Wide Inflammation

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Abstract

Elevated gene and protein expression levels of TLR4 and TREM2 were observed in APP/PS1 mice compared to wild-type mice.

TLR4 expression was persistently up-regulated after systemic inflammation induced by lipopolysaccharide (LPS).
TREM2 expression was significantly down-regulated in APP/PS1 mice following LPS treatment.
The imbalance between TLR4 and TREM2 may contribute to microglial over-activation and increased neuronal apoptosis.
Cognitive impairment in APP/PS1 mice was acutely worsened by LPS administration, indicating a potential role of systemic inflammation in Alzheimer's disease progression.
The findings suggest that TREM2 could serve as a potential therapeutic target for addressing systemic inflammation in Alzheimer's disease.

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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 Aβ. Similar alterations were observed in our in vitro experiment with β-amyloid(Aβ)-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. 1-42 1-42 1-42

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Imbalance of Microglial TLR4/TREM2 in LPS-Treated APP/PS1 Transgenic Mice: A Potential Link Between Alzheimer’s Disease and Systemic Inflammation

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