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

Paul J. Cheng-Hathaway, Erin G. Reed-Geaghan, Taylor R. Jay, Brad T. Casali, Shane M. Bemiller, Shweta S. Puntambekar, Victoria E. Von Saucken, Roxanne Y. Williams, J. Colleen Karlo, Miguel Moutinho, Guixiang Xu, Richard M. Ransohoff, Bruce Lamb, Gary E. Landreth

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Article number29
JournalMolecular Neurodegeneration
Volume13
Issue number1
DOIs
StatePublished - Jun 1 2018

Fingerprint

Myeloid Cells
Alzheimer Disease
Phenotype
Amyloid Plaques
Clustered Regularly Interspaced Short Palindromic Repeats
Alleles
Amyloid
Single Nucleotide Polymorphism
Disease Progression
Messenger RNA

Keywords

  • Alzheimer's disease
  • CRISPR/Cas9
  • Innate immunity
  • Neuroinflammation
  • Single nucleotide polymorphism
  • TREM2

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Cheng-Hathaway, P. J., Reed-Geaghan, E. G., Jay, T. R., Casali, B. T., Bemiller, S. M., Puntambekar, S. S., ... Landreth, G. E. (2018). The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. Molecular Neurodegeneration, 13(1), [29]. https://doi.org/10.1186/s13024-018-0262-8

The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. / Cheng-Hathaway, Paul J.; Reed-Geaghan, Erin G.; Jay, Taylor R.; Casali, Brad T.; Bemiller, Shane M.; Puntambekar, Shweta S.; Von Saucken, Victoria E.; Williams, Roxanne Y.; Karlo, J. Colleen; Moutinho, Miguel; Xu, Guixiang; Ransohoff, Richard M.; Lamb, Bruce; Landreth, Gary E.

In: Molecular Neurodegeneration, Vol. 13, No. 1, 29, 01.06.2018.

Research output: Contribution to journalArticle

Cheng-Hathaway, PJ, Reed-Geaghan, EG, Jay, TR, Casali, BT, Bemiller, SM, Puntambekar, SS, Von Saucken, VE, Williams, RY, Karlo, JC, Moutinho, M, Xu, G, Ransohoff, RM, Lamb, B & Landreth, GE 2018, 'The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease', Molecular Neurodegeneration, vol. 13, no. 1, 29. https://doi.org/10.1186/s13024-018-0262-8
Cheng-Hathaway PJ, Reed-Geaghan EG, Jay TR, Casali BT, Bemiller SM, Puntambekar SS et al. The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. Molecular Neurodegeneration. 2018 Jun 1;13(1). 29. https://doi.org/10.1186/s13024-018-0262-8
Cheng-Hathaway, Paul J. ; Reed-Geaghan, Erin G. ; Jay, Taylor R. ; Casali, Brad T. ; Bemiller, Shane M. ; Puntambekar, Shweta S. ; Von Saucken, Victoria E. ; Williams, Roxanne Y. ; Karlo, J. Colleen ; Moutinho, Miguel ; Xu, Guixiang ; Ransohoff, Richard M. ; Lamb, Bruce ; Landreth, Gary E. / The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. In: Molecular Neurodegeneration. 2018 ; Vol. 13, No. 1.
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AU - Cheng-Hathaway, Paul J.

AU - Reed-Geaghan, Erin G.

AU - Jay, Taylor R.

AU - Casali, Brad T.

AU - Bemiller, Shane M.

AU - Puntambekar, Shweta S.

AU - Von Saucken, Victoria E.

AU - Williams, Roxanne Y.

AU - Karlo, J. Colleen

AU - Moutinho, Miguel

AU - Xu, Guixiang

AU - Ransohoff, Richard M.

AU - Lamb, Bruce

AU - Landreth, Gary E.

PY - 2018/6/1

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N2 - 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.

AB - 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.

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KW - Neuroinflammation

KW - Single nucleotide polymorphism

KW - TREM2

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