TREM2 defects linked to neurodegeneration

TREM2-DAP12 dependent intracellular signaling pathways. Ligand binding and electrostatic interactions with DAP12 activates TREM2. TREM2 activation results in phosphorylation-dependent recruitment of signaling proteins that regulate a variety of downstream effectors, including gene transcription of inhibitors of pro-inflammatory cytokines. In addition, TREM2-DAP12 regulation of PI3K and RAS allows cross-talk with Toll-like Receptor (TLR) signaling pathways.

Immunological responses are in place to help defend our bodies from infection. When those responses are out of balance, the risk of disease goes up. Imbalances in neuronal immunity, for example, are strongly associated with neurodegenerative diseases. In a recent minireview published in the Journal of Biological Chemistry, Jochen Walter at the University of Bonn in Germany explores current research examining the triggering receptor expressed on myeloid cells, or TREM2, which plays a key role in regulating intracellular signaling pathways and is expressed in cells that contribute to innate immunity. The review discusses defects in the expression and activity of TREM2 and its co-receptor, DNAX-activating protein of 12 kDa, or DAP12, which are linked to neurodegenerative diseases and dementia.

The inflammatory response in the brain is maintained in part by microglia, brain phagocytes that scan and detect irregular pathogens or molecular patterns. Upon activation, microglia help to stimulate the generation of an immune response. However, chronic stimulation of the neuronal immune response has been observed in pathologies in the brain and frontotemporal diseases. Defects in TREM2 expression and regulation in microglia affect the innate immune response and may contribute to neuronal diseases.

TREM 2 and its co-receptor, DAP12, regulate signaling at the cell surface and are expressed in dendritic cells, osteoclasts and microglia. In the review, Walter focuses on specific mutations in TREM2 or DAP12 in relation to Nasu–Hakola disease, a rare, inherited disease which presents with bone fractures and early onset dementia, and he looks at the potential role of TREM2 in the pathogenesis of Alzheimer’s disease. Key hallmarks of the disease are the accumulation of amyloid-beta plaques and aggregation of the microtubule-associated protein tau. Walter highlights the genetic studies on amyloid-beta and tau accumulation in addition to studies of the most common risk factor for late-onset Alzheimer’s disease, the epsilon 4 allele of apolipoprotein E, or ApoE. According to Walter, in vitro studies show that ApoE is a ligand for TREM2, and other studies link TREM2 with amyloid-beta plaques and tau aggregation, further implicating the receptor in Alzheimer’s disease.

This review also highlights work with genetic knockout mice and knockdown studies of TREM2, which show increased levels of neuronal inflammation and associated risks for neuropathologies. Furthermore, genetic analyses of patients reveal that a single point mutation in TREM2 is associated with an increased risk for late-onset Alzheimer’s. While this point mutation is rare, Walter discusses additional studies implicating TREM2 in neurogenerative diseases and suggests that mechanistic studies examining the role of TREM2 are critical for future diagnosis and treatment of these diseases.

Christine C. Lee Christine C. Lee is a doctoral candidate in the department of biochemistry and molecular biology at the Johns Hopkins Bloomberg School of Public Health.