Recent genome wide methylation studies also revealed

Recent genome wide methylation studies also revealed that DNA methylation in peripheral leukocytes related to both aging and AD and could be exploited for identification of AD biomarkers (Li et al., 2016). Circulating leukocytes play an important role in the innate immune response against pathogens and numerous studies have shown that peripheral myeloid cells can infiltrate BRD-K4477 tissue and reduce the deposition of Aβ plaques (review in Zenaro et al., 2016). Furthermore, recent data indicate that infiltrating monocytes rather than resident microglia express TREM2, a receptor involved in myeloid cell phagocytosis, supporting the role of peripheral myeloid cells in AD pathogenesis (Jay et al., 2015). Thus, hypomethylation at CpG sites in intron 1 of TREM2 in leukocytes can be a biomarker of AD pathogenesis. Considering subtle changes (∼20%) in TREM2 expression or methylation with many control subjects overlapping with the cases, it is difficult to claim that TREM2 expression/methylation change by itself may be a “biomarker for AD”. However, it could be one of the elements of a panel of biomarkers for AD (Watanabe et al., 2015). There were several limitations of this study. Sample size was relatively small. We did not examine whether methylation rates of TREM2 in leukocytes are equivalent to those in the brain. Although several studies have shown that DNA methylation in peripheral blood often correlates with that in brain (Wockner et al., 2014, Davies et al., 2012), it should be verified whether the same results can be obtained in brain samples. Although there were no significant correlations between the TREM2 mRNA expression level or methylation rates and clinical characteristics of AD, multiple linear regression revealed that age and sex might influence both TREM2 mRNA expression level and methylation rates. Further research on the relationship among TREM2 and age and sex is needed. In conclusion, we reported for the first time that TREM2 mRNA expression was elevated and that TREM2 DNA methylation rates were decreased in peripheral leukocytes in AD subjects. These results suggest that hypomethylation at CpG sites in intron 1 of TREM2 in leukocytes can be a biomarker of AD pathogenesis. Our study may be an important step in understanding epigenetic mechanisms underlying AD pathogenesis.
Acknowledgments We wish to thank Ms. Chiemi Onishi for technical assistance. This work was partially supported by a Health and Labor Science Research Grant from the Japanese Ministry of Health, Labour and Welfare and a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, JSPS KAKENHI Grant Numbers 15K09808 and 16K21207.
Introduction Mild cognitive impairment (MCI) is a clinical transitional stage between normal aging and Alzheimer disease (AD) [1]. Approximate 15–30% MCI patients convert to AD annually. Although many efforts have been taken to prevent the conversion from MCI to AD [2], [3], there are few biomarkers to predict the progression of MCI.