Abstract
BackgroundThe 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.MethodsIn 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.ResultsAD 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.ConclusionsThese 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.
Highlights
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
Founder lines positive for the single nucleotide polymorphism (SNP) were crossed to the APPPS1–21 AD mouse model [26], generating APPPS1–21;Trem2+/R47H mice
Trem2 R47H impairs the myeloid cell response to amyloid pathology To determine whether the Trem2 R47H variant affects Trem2 expression, we evaluated Trem2 RNA levels in the brains of Trem2+/+, and Trem2+/R47H mice and found a significant 42% decrease in Trem2 RNA in Trem2+/R47H mice compared to Trem2+/+ mice (Additional file 2: Figure S1C)
Summary
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. Yuan et al postulate that the loss of plaque-associated myeloid cells promotes plaque expansion and damage to surrounding neurites in Trem deficient mice [9] In support of this hypothesis, Trem deficient AD mice exhibit enhanced amyloid pathology at late stages in disease [10, 11] accompanied by increased plaque-associated neuritic dystrophy [9, 11, 12]. At early stages of disease progression, Trem deficiency reduces amyloid burden [10, 13]
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