Variant TREM2 Signaling in Alzheimer's Disease

• Published in: Journal of molecular biology 2022-04, Vol.434 (7), p.167470-167470, Article 167470
• Main Authors: Olufunmilayo, Edward O., Holsinger, R.M. Damian
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; gene variants; Humans; lipoprotein; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; microglia; Microglia - metabolism; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Signal Transduction; TREM2
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2022.167470

[Display omitted] •TREM2 is an important receptor on microglial cells in the brain.•Variants of TREM2 have been associated with Alzheimer’s disease and other neurodegenerative diseases.•TREM2 activation leads to important downstream signaling events that may be perturbed in Alzheimer’s disease.•This review discusses the current knowledge of variant TREM2 signaling in Alzheimer’s disease, identifies gaps in our knowledge and proposes potential avenues for future studies. 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.