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

dc.contributor.authorCheng-Hathaway, Paul J.
dc.contributor.authorReed-Geaghan, Erin G.
dc.contributor.authorJay, Taylor R.
dc.contributor.authorCasali, Brad T.
dc.contributor.authorBemiller, Shane M.
dc.contributor.authorPuntambekar, Shweta S.
dc.contributor.authorvon Saucken, Victoria E.
dc.contributor.authorWilliams, Roxanne Y.
dc.contributor.authorKarlo, J. Colleen
dc.contributor.authorMoutinho, Miguel
dc.contributor.authorXu, Guixiang
dc.contributor.authorRansohoff, Richard M.
dc.contributor.authorLamb, Bruce T.
dc.contributor.authorLandreth, Gary E.
dc.contributor.departmentAnatomy and Cell Biology, School of Medicineen_US
dc.date.accessioned2019-02-14T15:17:11Z
dc.date.available2019-02-14T15:17:11Z
dc.date.issued2018-06-01
dc.description.abstractBACKGROUND: 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.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationCheng-Hathaway, P. J., Reed-Geaghan, E. G., Jay, T. R., Casali, B. T., Bemiller, S. M., Puntambekar, S. S., von Saucken, V. E., Williams, R. Y., Karlo, J. C., Moutinho, M., Xu, G., Ransohoff, R. M., Lamb, B. T., … Landreth, G. E. (2018). The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. Molecular neurodegeneration, 13(1), 29. doi:10.1186/s13024-018-0262-8en_US
dc.identifier.urihttps://hdl.handle.net/1805/18370
dc.language.isoen_USen_US
dc.publisherBMCen_US
dc.relation.isversionof10.1186/s13024-018-0262-8en_US
dc.relation.journalMolecular neurodegenerationen_US
dc.rightsAttribution 3.0 United States
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/
dc.sourcePMCen_US
dc.subjectAlzheimer’s diseaseen_US
dc.subjectCRISPR/Cas9en_US
dc.subjectInnate immunityen_US
dc.subjectNeuroinflammationen_US
dc.subjectSingle nucleotide polymorphismen_US
dc.subjectTREM2en_US
dc.titleThe Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's diseaseen_US
dc.typeArticleen_US
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