Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer's disease.
A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10(-10)).
Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease.
Our results suggest that the TREM2p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson's disease in addition to Alzheimer's disease.
Most importantly, we show that the TREM2-containing module is significantly enriched for genes genetically implicated in Alzheimer's disease, multiple sclerosis, and motor neuron disease, implying that these diseases share common pathways centered on microglia and that among the genes identified are possible new disease-relevant genes.
Together, these data demonstrate γ-secretase-mediated intramembranous proteolysis of TREM2 and functionally link two Alzheimer disease-associated proteins in one signaling pathway.
Our data corroborate and extend previous findings to include an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants may play a role in neurodegenerative diseases in general.
In conclusion, the association between TREM2 and both parental history of AD and younger maternal age of AD onset provide additional support for the role of TREM2 in AD and illustrate the importance of considering family history in AD study design.
Recent genetic studies have reported the occurrence of point mutations in TREM-2 that correlate with a dramatically increased risk for the development of neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia, and Parkinson's disease.
Recently, a rare missense variant (p.R47H) in the microglial activating gene TREM2 was found to increase the risk of several neurodegenerative diseases, including Alzheimer disease.
Recent studies have reported that a rare nonsynonymous variant rs75932628-T in the TREM2 gene is associated with increased risk of Alzheimer's disease and Parkinson's disease (PD) in European-descended populations.
As a result, none of these 3 variants were identified in all subjects, however, 1 novel variant (p.A130V) in TREM2 and 4 novel variants (p.Q860H, p.T837K, p.S843G, and p.V836V) in UNC5C were detected in unrelated patients with late-onset AD.
A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.