Abstract
BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia.MethodsTo investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches.ResultsWhile mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity.ConclusionOur findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.
Highlights
Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD)
Trem2Y38C/Y38C mouse model generation To examine the consequences of a putative loss of function Triggering Receptor expressed on myeloid cells 2 (Trem2) variant, Trem2Y38C/Y38C mice containing the NHD Trem2 Y38C variant were generated using CRIS PR/Cas9 to introduce a point mutation in the endogenous Trem2 gene, resulting in a substitution of tyrosine to cystine at position 38 (Fig. 1a)
Since an artifactual alternate splice variant has been reported in the Trem2 R47H variant mouse model that resulted in reduced Trem2 mRNA and protein expression [29], we evaluated the presence of alternate splice variants in the Trem2Y38C/Y38C mouse model but none were found
Summary
Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem variants like Y38C, are associated with development of early onset dementia with white matter pathology. It is not known how these Trem species, predisposes individuals to presenile dementia. Individuals with the rare R47H variant of TREM2 have substantial risk of developing late onset Alzheimer’s disease (AD) [7, 8] This mutation alters the ligand binding region of TREM2, conferring loss of function [9]. The effects of Y38C, in vivo, on brain homeostasis in the presence and absence of pathology have yet to be determined
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