Evidence of Trem2 Variant Associated with Triple Risk of Alzheimer’s Disease

Abstract

Alzheimer’s disease is one of the main causes of dementia among elderly individuals and leads to the neurodegeneration of different areas of the brain, resulting in memory impairments and loss of cognitive functions. Recently, a rare variant that is associated with 3-fold higher risk of Alzheimer’s disease onset has been found. The rare variant discovered is a missense mutation in the loop region of exon 2 of Trem2 (rs75932628-T, Arg47His). The aim of this study was to investigate the evidence for potential structural and functional significance of Trem2 gene variant (Arg47His) through molecular dynamics simulations. Our results showed the alteration caused due to the variant in TREM2 protein has significant effect on the ligand binding affinity as well as structural configuration. Based on molecular dynamics (MD) simulation under salvation, the results confirmed that native form of the variant (Arg47His) might be responsible for improved compactness, hence thereby improved protein folding. Protein simulation was carried out at different temperatures. At 300K, the deviation of the theoretical model of TREM2 protein increased from 2.0 Å at 10 ns. In contrast, the deviation of the Arg47His mutation was maintained at 1.2 Å until the end of the simulation (t = 10 ns), which indicated that Arg47His had reached its folded state. The mutant residue was a highly conserved region and was similar to “immunoglobulin V-set” and “immunoglobulin-like folds”. Taken together, the result from this study provides a biophysical insight on how the studied variant could contribute to the genetic susceptibility to Alzheimer’s disease.

The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia

“…The R47H variant is located within the extracellular immunoglobulin-like domain and recent results support a significant effect on ligand binding affinity as well as structural configuration of TREM2 [31], with possible subsequent signaling dysregulation. Here we demonstrate that the R47H variant is associated with distinct signaling in cases with AD.…”

Lipid transporter Spns2 promotes microglia pro‐inflammatory activation in response to amyloid‐beta peptide

“…Microglia depletion/inhibition in animal models of AD ameliorates memory loss in adult mice (Asai et al, ). In addition, Genomic wide association studies (GWAS) have identified variants of several immune genes are risk factors for late‐onset AD including CD33 and TREM2 (Abduljaleel et al, ; Hollingworth et al, ; Jonsson et al, ; Naj et al, ; Painter et al, ; Wang et al, ). A most recent three‐stage case‐controlled study of 85,133 subjects identified three new genome‐wide significant nonsynonymous variants in PLCG2, ABI3, TREM2 (Sims et al, ).…”

Assessment of TREM2 rs75932628 association with amyotrophic lateral sclerosis in a Chinese population

“…Recent studies identified a rare TREM2 rs75932628 variant (p.R47H) as a risk factor for AD, suggesting that the protein plays an important role in neurodegeneration [6,19,20]. Studies also identified the association with diseased risk for frontotemporal dementia (FTD) [16] and ALS [15].…”