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Alzheimers Dement. 2017 Apr;13(4):381-387. doi: 10.1016/j.jalz.2016.07.004. Epub 2016 Aug 9.

Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
2
Department of Neurology, Harvard Medical School, and Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA, USA.
3
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
4
Department of Neurology, Harvard Medical School, and Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA, USA. Electronic address: tanzi@helix.mgh.harvard.edu.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mcolonna@pathology.wustl.edu.

Abstract

INTRODUCTION:

TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial.

METHODS:

We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes.

RESULTS:

We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte-derived dendritic cells.

DISCUSSION:

Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.

KEYWORDS:

Alzheimer's disease; HDL; LDL; Lipoprotein; Microglia; Monocyte; TREM2

PMID:
27520774
PMCID:
PMC5299056
DOI:
10.1016/j.jalz.2016.07.004
[Indexed for MEDLINE]
Free PMC Article

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