Triggering receptor expressed on myeloid cells 2 activation downregulates toll‐like receptor 4 expression and ameliorates cognitive impairment in the Aβ1‐42‐induced Alzheimer's disease mouse model

Increasing evidence suggests that changes in the triggering receptor expressed on myeloid cells 2 (TREM2) is closely correlated with the pathological development of Alzheimer's disease (AD). However, the biological function and related role of this change remain poorly understood. Higher TREM2 expression has been reported in the brain of AD patients than in normal controls. Here, levels of TREM2 gene and protein levels were observed to be higher in both cortex and hippocampus of the Aβ1-42 -induced AD mice than in those of the wild type mice. Together with in vitro experimental data, we found that the anti-inflammatory role of TREM2 was, to some extent, limited and potentially counteracted by the hyperactive toll-like receptor 4 (TLR4) in the AD mice. In this context, Interleukin 4 (IL-4), as an agonist of TREM2, was administered to the AD mice to persistently activate TREM2. Interestingly, TREM2 activation in IL-4-treated AD mice led to an elevation in lysosomes and microtubule-associated protein 1 light chain 3 (LC3) II/I expression, demonstrating that the level of microglia autophagy was increased. Increased autophagy significantly downregulated the expression levels of caspase recruitment domain-containing protein 9 (CARD9) and TLR4, potentially weakening the CARD9-TLR4 pathway and suppressing the TLR4-mediated pro-inflammatory effect in IL-4-treated AD mice. Furthermore, data acquired from Morris water maze testing indicated that IL-4 administration could ameliorate cognitive impairment in the AD mice. In conclusion, the findings from in vitro and in vivo experiments suggest that TREM2 might represent a potential drug target to treat neuroinflammation in AD.