TREM2 Mediates Microglial Anti-Inflammatory Activations in Alzheimer’s Disease: Lessons Learned from Transcriptomics

Abstract

Alzheimer’s disease (AD) is a lethal neurodegenerative disorder primarily affecting the aged population. The etiopathogenesis of AD, especially that of the sporadic type, remains elusive. The triggering receptor expressed on myeloid cells 2 (TREM2), a member of TREM immunoglobulin superfamily, plays a critical role in microglial physiology. Missense mutations in human TREM2 are determined as genetic risk factors associated with the development of sporadic AD. However, the roles of TREM2 in the pathogenesis of AD are still to be established. In this review, we outlined the influence of Trem2 on balance of pro- and anti-inflammatory microglial activations from a perspective of AD mouse model transcriptomics. On this basis, we further speculated the roles of TREM2 in different stages of AD, which may shed light to the development of TREM2-targeted strategy for the prevention and treatment of this neurodegenerative disorder.

Beyond Activation: Characterizing Microglial Functional Phenotypes

“…This microglial subset presented a morphologically dystrophic phenotype. Interestingly, PU.1, which was proposed to be a key transcription factor for regulating TMEM119 expression [45], also acts as an upstream regulator of TREM2 [48], suggesting a functional role of TMEM119 in the pathological changes associated with Alzheimer's disease. Genetic targeting of TREM2 induced the restored expression of homeostatic microglial markers, such as TMEM119 and P2RY12, concomitant with the G-proteincoupled receptor (GPR)-34 [49], which is necessary for keeping microglial morphology in a homeostatic non-phagocytic phenotype [50].…”

Multi-Omics Analysis of Microglial Extracellular Vesicles From Human Alzheimer’s Disease Brain Tissue Reveals Disease-Associated Signatures

“…DAM populations are characterized by the loss of a homeostatic transcriptional signature, including decreases in purinergic 2Y receptor 12 (P2RY12), P2RY13, transmembrane protein 119 (TMEM119), CX3C chemokine receptor 1 (CX3CR1), and others, and activation of genes responsible for either proinflammatory microglia activation (Stage 1 DAM) or a neurodegeneration restrictive phenotype (Stage 2 DAM). Upregulation of apoE, ferritin heavy chain-1 (FTH-1), beta-2-microglobulin (B2m), major histocompatibility complex class I (MHC class 1), and DAP12 are changes associated with the Stage 1 DAM transcriptome profile, while increases in the triggering receptor expressed on myeloid cells 2 ( TREM 2) and exosomal markers CD63 and CD9 are part of the Stage 2 DAM program ( Deczkowska, et al, 2018 ; Xue and Du, 2021 ). Upregulation of exosomal markers suggests that an increase in exosome production may help to resolve inflammation; on the other hand, microglial EVs, specifically the neutral sphingomyelinase 2 (nSMase2)-dependent exosomal population, take part in spreading tau pathology in vitro and in mouse models of tauopathy ( Asai, et al, 2015 ; Maphis, et al, 2015 ).…”

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

“…Furthermore, in several brain homeostatic pathways, including lipid transfer, synaptic integrity and plasticity, glucose metabolism and cerebrovascular activity, APOE4 is either pathogenic or a decreasing factor of performance [ 8 , 9 , 10 , 11 ]. In turn, TREM2 is a very abundant receptor on the surface of microglia and plays an important role in its activation and regulation [ 13 , 14 ]. Certain mutations can condition the affinity of TREM2 for its ligands, decreasing phagocytosis of Aβ peptide by microglia and promoting a systemic inflammatory response.…”

“…Type two diabetes mellitus (T2DM) and LOAD have become worldwide pandemics, with recent projections indicating that they will get worse in the coming decades. In this respect, obesity, T2DM and associated comorbidities have been described to be involved in the development of LOAD [ 14 ]. Thus, LOAD has been recently described as a “metabolic disease”, related with the inefficient utilization of glucose by the brain and associated with insulin resistance and chronic mild inflammation in the brain [ 15 , 16 , 17 , 18 , 19 , 20 ].…”