TitleRare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression.
Publication TypeJournal Article
Year of Publication2016
AuthorsSirkis DW, Bonham LW, Aparicio RE, Geier EG, Ramos EMarisa, Wang Q, Karydas A, Miller ZA, Miller BL, Coppola G, Yokoyama JS
JournalActa Neuropathol Commun
Date Published2016 09 02
KeywordsAged, Alzheimer Disease, Case-Control Studies, Cell Membrane, Cohort Studies, Female, Genetic Predisposition to Disease, HEK293 Cells, Humans, Male, Membrane Glycoproteins, Polymorphism, Single Nucleotide, Receptors, Immunologic

Rare variation in TREM2 has been associated with greater risk for Alzheimer's disease (AD). TREM2 encodes a cell surface receptor expressed on microglia and related cells, and the R47H variant associated with AD appears to affect the ability of TREM2 to bind extracellular ligands. In addition, other rare TREM2 mutations causing early-onset neurodegeneration are thought to impair cell surface expression. Using a sequence kernel association (SKAT) analysis in two independent AD cohorts, we found significant enrichment of rare TREM2 variants not previously characterized at the protein level. Heterologous expression of the identified variants showed that novel variants S31F and R47C displayed significantly reduced cell surface expression. In addition, we identified rare variant R136Q in a patient with language-predominant AD that also showed impaired surface expression. 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.

Alternate JournalActa Neuropathol Commun
PubMed ID27589997
PubMed Central IDPMC5010724
Grant ListP50 AG023501 / AG / NIA NIH HHS / United States
K01 AG049152 / AG / NIA NIH HHS / United States
P30 NS062691 / NS / NINDS NIH HHS / United States
K23 AG048291 / AG / NIA NIH HHS / United States
F32 AG050404 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States