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Acta Neuropathol Commun. 2016 Sep 2;4(1):98. doi: 10.1186/s40478-016-0367-7.

Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression.

Author information

1
Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, 94720, USA.
2
Memory and Aging Center, UCSF, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
3
Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
4
Memory and Aging Center, UCSF, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA. jennifer.yokoyama@ucsf.edu.

Abstract

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.

KEYWORDS:

Alzheimer’s disease; Genetics; Nasu-Hakola disease; TREM2

PMID:
27589997
PMCID:
PMC5010724
DOI:
10.1186/s40478-016-0367-7
[Indexed for MEDLINE]
Free PMC Article

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