Our findings shed new light on the relationship between TREM2/DNAX-activating protein 12 (DAP12) signaling and Wnt/β-catenin signaling and provide clues as to how reduced TREM2 function might impair microglial survival in AD pathogenesis.
Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful.
Together, these data demonstrate γ-secretase-mediated intramembranous proteolysis of TREM2 and functionally link two Alzheimer disease-associated proteins in one signaling pathway.
In this review, we summarize increases in our understanding of the involvement of TREM2 and microglia in AD development that may open new therapeutic strategies targeting the immune system to influence AD pathogenesis.
Down-regulated mRNAs include those encoding complement factor-H (CFH), an SH3-proline-rich multi-domain-scaffolding protein of the postsynaptic density (SHANK3), and the triggering receptor expressed in myeloid/microglial cells (TREM2), as is observed in sporadic AD brain.
TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood.
These findings indicate that TREM2-mediated protection in AD is at least partially dependent on the reservation of microglial phagocytic functions, emphasizing the importance of early therapeutic interventions for this devastating disease.
Although TREM2 mutation is reported to be related to Nasu-Hakola disease and Alzheimer's disease, little is known about the association between TREM2 and gliomas.
In conclusion, the association between TREM2 and both parental history of AD and younger maternal age of AD onset provide additional support for the role of TREM2 in AD and illustrate the importance of considering family history in AD study design.
Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)<sup>-/-</sup> Tg-AD reveals that the DAM program is activated in a two-step process.
TYROBP/DAP12 forms complexes with ectodomains of immune receptors (TREM2, SIRPβ1, CR3) associated with Alzheimer's disease (AD) and is a network hub and driver in the complement subnetwork identified by multi-scale gene network studies of postmortem human AD brain.
TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration.
The results provide insight into TREM2-related mechanisms that may be associated with AD in humans and may aid future development of disease-modifying pharmacological treatments targeting TREM2.
We demonstrate that TREM2 deficiency has opposing effects on AD-related pathologies at early and late stages of disease progression, unifying previous work in the field.