Triggering receptor expressed on myeloid cells 2 activation downregulates toll‐like receptor 4 expression and ameliorates cognitive impairment in the Aβ_1‐42‐induced Alzheimer's disease mouse model

Abstract

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.

Discovery of Active Ingredients Targeted TREM2 by SPR Biosensor-UPLC/MS Recognition System, and Investigating the Mechanism of Anti-Neuroinflammatory Activity on the Lignin-Amides from Datura metel Seeds

“…According to the literature, the effects of LDS on TREM2 may be related to its inhibition of the production of inflammatory cytokines and the clearance of damaged cell fragments [ 49 ]. The TREM2 protein may also play a role by down-regulating CARD9 (caspase recruitment domain protein 9)-TRL4 and PI3K (phosphatidylinositol 3 kinase)-AKT (protein kinase B)-NF-κB (nuclear factor activated B cells κ-Light chain reinforcement) signaling pathways, which provided ideas for further research [ 50 , 51 ]. Meanwhile, TREM2 may affect the occurrence of CNS (central nervous system) diseases, such as AD, Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), stroke, as well as traumatic brain injury [ 52 ].…”

Alzheimer's Disease Investigated via Gene-Environment Interactions, Biochemical Pathways, Cellular Processes, and Disease Phenotype Variability

“…Differences in the extent of amyloid-beta deposition, tau pathology, neuroin ammation, synaptic dysfunction, and neurodegeneration may in uence disease phenotype [160]. Variability in the age of onset, symptom severity, and disease progression among individuals carrying similar mutations in the TREM2 gene can be attributed to a complicated interaction of genetic, environmental, neurobiological, cognitive, and other factors [147,159].…”

A systematic review of the role of TREM2 in Alzheimer’s disease

“…This highlighted TREM2's potential anti-inflammatory effect, suppressing TLR4-mediated pro-inflammatory responses. [60] A complex interplay emerged in the tau model. TREM2 overexpression in P301S mice reduced the level of several transcripts, including Tnf-α, Il-1β, and Il-6, while elevating microglial M2 phenotype markers like Arg1, Retnla, Il-4, and Il-10.…”