TREM2, triggering receptor expressed on myeloid cells 2, is a surface receptor crucial for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis [1]. It has been associated with multiple pathways, such as the mammalian target of rapamycin (mTOR) signaling pathway which impacts ATP levels and biosynthetic pathways [1]. TREM2 is of great biological importance, especially in relation to Alzheimer's disease (AD), where its hypomorphic variants elevate the disease risk [1]. Genetic models, like KO/CKO mouse models, have been instrumental in studying TREM2.

In AD, TREM2-deficient mice with AD-like pathology display abnormal autophagy due to defective mTOR signaling, affecting microglial metabolic fitness [1]. This shows TREM2's role in sustaining microglial energetic and biosynthetic metabolism during AD [1]. In another study, TREM2-deficient mice with amyloid-β pathology had issues with microglial clustering around plaques and increased plaque-adjacent neuronal dystrophy, which was improved by dietary cyclocreatine [1]. Also, in mouse models of amyloid β (Aβ) accumulation, defective TREM2 function exacerbates tissue damage, while TREM2 overexpression attenuates pathology [2].

In conclusion, TREM2 is essential for maintaining microglial metabolic fitness and proper microglial responses in the context of AD. Gene knockout mouse models have been pivotal in revealing these functions, providing insights into the role of TREM2 in AD pathogenesis and potentially guiding the development of new AD therapies.

References:

1. Ulland, Tyler K, Song, Wilbur M, Huang, Stanley Ching-Cheng, Holtzman, David M, Colonna, Marco. . TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. In Cell, 170, 649-663.e13. doi:10.1016/j.cell.2017.07.023. https://pubmed.ncbi.nlm.nih.gov/28802038/

2. Wang, Shoutang, Mustafa, Meer, Yuede, Carla M, Schwabe, Tina, Colonna, Marco. . Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. In The Journal of experimental medicine, 217, . doi:10.1084/jem.20200785. https://pubmed.ncbi.nlm.nih.gov/32579671/