Format

Send to

Choose Destination
Mol Neurodegener. 2018 Jun 1;13(1):29. doi: 10.1186/s13024-018-0262-8.

The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease.

Author information

1
Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA.
2
Department of Anatomy and Cell Biology, Indiana University, School of Medicine, Indianapolis, IN, 46202, USA.
3
Paul and Carole Stark Neurosciences Research Institute, Indiana University, School of Medicine, Indianapolis, IN, 46202, USA.
4
Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, IN, 46202, USA.
5
Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
6
Third Rock Ventures, Boston, MA, 02116, USA.
7
Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA. glandret@iu.edu.
8
Department of Anatomy and Cell Biology, Indiana University, School of Medicine, Indianapolis, IN, 46202, USA. glandret@iu.edu.
9
Paul and Carole Stark Neurosciences Research Institute, Indiana University, School of Medicine, Indianapolis, IN, 46202, USA. glandret@iu.edu.

Abstract

BACKGROUND:

The R47H variant of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) confers greatly increased risk for Alzheimer's disease (AD), reflective of a central role for myeloid cells in neurodegeneration. Understanding how this variant confers AD risk promises to provide important insights into how myeloid cells contribute to AD pathogenesis and progression.

METHODS:

In order to investigate this mechanism, CRISPR/Cas9 was used to generate a mouse model of AD harboring one copy of the single nucleotide polymorphism (SNP) encoding the R47H variant in murine Trem2. TREM2 expression, myeloid cell responses to amyloid deposition, plaque burden, and neuritic dystrophy were assessed at 4 months of age.

RESULTS:

AD mice heterozygous for the Trem2 R47H allele exhibited reduced total Trem2 mRNA expression, reduced TREM2 expression around plaques, and reduced association of myeloid cells with plaques. These results were comparable to AD mice lacking one copy of Trem2. AD mice heterozygous for the Trem2 R47H allele also showed reduced myeloid cell responses to amyloid deposition, including a reduction in proliferation and a reduction in CD45 expression around plaques. Expression of the Trem2 R47H variant also reduced dense core plaque number but increased plaque-associated neuritic dystrophy.

CONCLUSIONS:

These data suggest that the AD-associated TREM2 R47H variant increases risk for AD by conferring a loss of TREM2 function and enhancing neuritic dystrophy around plaques.

KEYWORDS:

Alzheimer’s disease; CRISPR/Cas9; Innate immunity; Neuroinflammation; Single nucleotide polymorphism; TREM2

PMID:
29859094
PMCID:
PMC5984804
DOI:
10.1186/s13024-018-0262-8
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center