The TREM2 Receptor Puzzle in Alzheimer’s Disease Assembling the Pieces

Alzheimer's disease (AD) is a neurological ailment that induces memory loss and cognitive deficiencies in patients, eventually impairing their learning and spatial skills. AD is the principal reason for dependency and incapacity in the elderly population, among many other neurodegenerative disorders. The two prominent pathological biomarkers of AD are aberrant neurofibrillary tau tangle deposition and amyloid plaques (Aβ peptides). In AD, microglia are triggered due to Aβ plaque deposition, potentially promoting pro-inflammatory microglial activation. Triggering receptor expressed on myeloid cells 2 (TREM2) is of major importance for sustaining the metabolic efficiency of microglia under stress, allowing them to fully develop their DAM profiles and ultimately preserving the inflammatory response to disease driven by Aβ plaque. Transmembrane receptor TREM2 is expressed in microglia, monocytes and myeloid cells, and its association with AD points to the possibility that immunological and inflammatory pathways play a more active role in the disease's progression than in its incidence. In addition, multiple rare point variations in TREM2 genes have also been discovered that pose a significant risk factor for early-onset dementia. Ever since, a developing collection of research on TREM2 has centred on defining its role in the pathogenesis of AD. In this chapter, we describe current developments in our understanding of TREM2's function in microglial pathophysiology associated with AD, as well as signalling pathways triggered by TREM2 ligands and their association with AD pathological hallmarks, Aβ and tau proteins.