Trem2-flox Mouse

TREM2, Triggering receptor expressed on myeloid cells 2, is a surface receptor on myeloid cells. It's crucial for microglial responses to neurodegeneration, including processes like proliferation, survival, clustering, and phagocytosis [1]. It has been implicated in multiple pathways related to metabolism, such as the mammalian target of rapamycin (mTOR) signaling pathway, influencing ATP levels and biosynthetic pathways [1]. TREM2 is of great biological importance, especially in neurodegenerative diseases, as well as in tumor microenvironments and liver-related diseases. Genetic models, like gene knockout (KO) mouse models, have been instrumental in studying its functions.

In Alzheimer's disease (AD), TREM2-deficient mice with AD-like pathology show abnormal autophagy due to defective mTOR signaling, resulting in metabolic derailment. Dietary cyclocreatine can offset these effects, restoring microglial clustering around plaques and reducing plaque-adjacent neuronal dystrophy, indicating TREM2's role in maintaining microglial metabolic fitness during AD [1]. In glioblastomas (GBM), genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo, suggesting a distinct immunoprotective role of TREM2 in central nervous system cancers compared to peripheral cancers [2]. In non-alcoholic fatty liver disease (NAFLD) and sepsis, Trem2-deficient macrophages release exosomes that impair hepatocytic mitochondrial structure and energy supply, accelerating NAFLD progression and sepsis susceptibility in a mouse model, while TREM2 overexpression in liver macrophages improves the outcome [3].

In conclusion, TREM2 is essential for maintaining microglial metabolic fitness, especially in AD. It also plays distinct roles in different types of cancers and in the coordination between hepatocyte-macrophage metabolism in NAFLD and sepsis. The use of KO mouse models has significantly advanced our understanding of TREM2's functions in these disease conditions, providing potential targets for therapeutic interventions.