Journal article
The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease
Molecular neurodegeneration, Vol.13(1), pp.29-12
06/01/2018
DOI: 10.1186/s13024-018-0262-8
PMCID: PMC5984804
PMID: 29859094
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 TREIV12 R47H variant increases risk for AD by conferring a loss of TREM2 function and enhancing neuritic dystrophy around plaques.
Details
- Title: Subtitle
- The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease
- Creators
- Paul J. Cheng-Hathaway - Case Western Reserve UniversityErin G. Reed-Geaghan - Case Western Reserve UniversityTaylor R. Jay - Case Western Reserve UniversityBrad T. Casali - Case Western Reserve UniversityShane M. Bemiller - Indiana University – Purdue University IndianapolisShweta S. Puntambekar - Indiana University – Purdue University IndianapolisVictoria E. von Saucken - Indiana University – Purdue University IndianapolisRoxanne Y. Williams - Indiana University – Purdue University IndianapolisJ. Colleen Karlo - Case Western Reserve UniversityMiguel Moutinho - Indiana University – Purdue University IndianapolisGuixiang Xu - Indiana University – Purdue University IndianapolisRichard M. Ransohoff - Cleveland Clinic Lerner College of MedicineBruce T. Lamb - Indiana University – Purdue University IndianapolisGary E. Landreth - Indiana University – Purdue University Indianapolis
- Resource Type
- Journal article
- Publication Details
- Molecular neurodegeneration, Vol.13(1), pp.29-12
- DOI
- 10.1186/s13024-018-0262-8
- PMID
- 29859094
- PMCID
- PMC5984804
- NLM abbreviation
- Mol Neurodegener
- ISSN
- 1750-1326
- eISSN
- 1750-1326
- Publisher
- Springer Nature
- Number of pages
- 12
- Grant note
- Alzheimer's Association T32 GM725039 / Medical Scientist Training Program training grant F30 AG055261; F31 AG048704 / NIA National Service Research Award T32 NS077888 / CWRU Neurodegenerative Diseases training grant R01 AG051495; AG050597; U54 AG054345 / NIA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA)
- Language
- English
- Date published
- 06/01/2018
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9985113010402771
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