We found that CX3CL1 and TREM2, two genes related to neuroinflammation, are more highly expressed in brain regions with pronounced vulnerability to AD-related changes, such as the hippocampus, and that the expression levels reflect the course of the disease, whereas regions with low vulnerability to AD, seemed generally less affected by neuroinflammation.
These data suggest a functionally important role for TREM2(+) macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology.
In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.
Although, rs75932628 in triggering receptor expressed on myeloid cells 2 (TREM2) was shown to increase the risk for Alzheimer's disease, there is no agreement on the association between this variant and the risk for amyotrophic lateral sclerosis (ALS).
Several TREM2 mutations have been identified recently that increase the risk of Alzheimer's disease, Frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis.
TREM2 is an innate immune receptor that regulates microglial cytokine production and phagocytosis, implying that dysregulation of these processes may be involved in AD pathology, with implications for disease management.
Although R47H mutation in AD affected the glycosylation and normal trafficking of TREM2 less, the detailed pattern of glycosylated TREM2 differs from that of the wild type, thus suggesting that precise regulation of TREM2 glycosylation is impaired when arginine at 47 is mutated to histidine.
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).
The results suggest rare TREM2 variants enriched in AD may be associated with altered TREM2 function and that AD risk may be conferred, in part, from altered TREM2 surface expression.
Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD.
Our results indicated that p.H157Y was associated with an increased risk of AD (OR=3.65, 95% CI: 1.61-8.28; P=0.002), further establishing TREM2 as an important susceptibility gene for this disease.
The previously reported functional mutation rs75932628-T (p.R47H) in the triggering receptor expressed on myeloid cells 2 (TREM2) is a genetic risk factor for Alzheimer's disease, Parkinson's disease (PD) and frontotemporal dementia, in European populations.
TREM2 is a transmembrane protein involved in innate immunity and is selectively expressed by microglia and genetically linked to AD and other neurodegenerative disorders.
Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer's disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function.
Although TREM2 mutation is reported to be related to Nasu-Hakola disease and Alzheimer's disease, little is known about the association between TREM2 and gliomas.
Our study suggests that Vps35/retromer is responsible for recycling of Trem2 in the regulation of microglial function such as proinflammatory responses, whereas R47H mutation impairs Trem2 trafficking, which might contribute to AD.