Correlation of gene expression with well-established AD-related factors, such as α-, β-, and γ-secretase activities, brain amyloid-β42 levels, and cerebrospinal fluid biomarkers, revealed a positive correlation between β-secretase activity and the expression of TREM2 and BIN1.
Crucially, we also show that the Alzheimer's disease-associated H157YTREM2 variant was shed more rapidly than wild type from HEK293 cells, possibly by a novel, batimastat- and ADAM10-siRNA-independent, sheddase activity.
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.
Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer's disease.
Emerging evidence from protein binding assays suggests that APOE binds to TREM2 and APOE-containing lipoproteins in the brain as well as periphery, and are putative ligands for TREM2, thus raising the possibility of an APOE-TREM2 interaction modulating different aspects of AD pathology, potentially in an isoform-specific manner.
Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful.
Finally, constitutive deletion of Rev-erbα in the 5XFAD model of AD decreased amyloid plaque number and size and prevented plaque-associated increases in disease-associated microglia markers including TREM2, CD45, and Clec7a.
Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.
Furthermore, recent identification of a low frequency mutation in the gene encoding the triggering receptor expressed in myeloid cells 2 protein (TREM2) confers increased risk of AD in LOAD cohorts with an effect size similar to that for APOE, until recently the only identified genetic risk factor associated with LOAD [9,10(••)] (Figure 1).
Furthermore, the associations of APOE and TREM2 with AD were highly significant, even in gene-based rare allele analysis, which implies that further deep sequencing of these genes is required in AD heritability studies.
Genetic mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to a variety of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Parkinson's disease.
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD).
Genome-wide association studies have linked variants in TREM2 (triggering receptor expressed on myeloid cells 2) and TREML2 with Alzheimer disease (AD) and AD endophenotypes.
Given recent findings of enrichment of rare TREM2 variants (including R47C) in Alzheimer's disease, it is notable that we detected a homozygous TREM2R47C carrier presenting with an FTD rather than an Alzheimer's disease phenotype.
Glial expression of TREM2/TYROBP exacerbated tau-mediated neurodegeneration and synergistically affected pathways underlying late-onset AD pathology, while neuronal Aβ42 and glial TREM2/TYROBP synergistically altered expression of the genes in synaptic function and immune modules in AD.
Here, we present data demonstrating increased DNA methylation in the superior temporal gyrus in Alzheimer's disease brain at a CpG site located 289 bp upstream of the transcription start site of the TREM2 gene in 3 independent study cohorts using 2 different technologies (Illumina Infinium 450K methylation beadchip and pyrosequencing).
Here, we review the expression, distribution, and function of CD200, CX3CL1, and TREM2 in regulating neuron-microglia interactions under physiological conditions as well as in AD.