Variant TREM2 Signaling in Alzheimer's Disease

Alzheimer's disease is the most common form of dementia, accounting for as much as three-quarters of cases globally with individuals in low- and middle-income countries being worst affected. Numerous risk factors for the disease have been identified and our understanding of gene-environment interactions have shed light on several gene variants that contribute to the most common, sporadic form of Alzheimer's disease. Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is an important receptor that is crucial to the functioning of microglial cells, and variants of this protein have been found to be associated with a significantly increased risk of Alzheimer's disease. Several studies have elucidated the signaling processes involved in the normal functioning of the TREM2 receptor. However, current knowledge of the idiosyncrasies of the signaling processes triggered by stimulation of the variants of this receptor is limited. In this review, we examine the existing literature and highlight the effects that various receptor variants have on downstream signaling processes and discuss how these perturbations may affect physiologic processes in Alzheimer's disease. Despite the fact that this is a territory yet to be fully explored, the studies that currently exist report mostly quantitative effects on signaling. More mechanistic studies with the aim of providing qualitative results in terms of downstream signaling among these receptor variants are warranted. Such studies will provide better opportunities of identifying therapeutic targets that may be exploited in designing new drugs for the management of Alzheimer's disease.