Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice

Abstract

AbstractBackgroundTriggering 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). TheTrem2variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linkedTrem2variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how theseTrem2species, predisposes individuals to presenile dementia.MethodsTo investigate ifTrem2Y38C or loss ofTrem2alters neuronal function we generated a novel mouse model to introduce the NHDTrem2Y38C variant in murineTrem2using CRISPR/Cas9 technology.Trem2Y38C/Y38CandTrem2−/−mice were assessed forTrem2expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches.ResultsWhile mice harboring theTrem2Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopiedTrem2−/−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 thatTrem2Y38C disrupts normal TREM2 functions.Trem2Y38C/Y38CandTrem2−/−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 withTREM2variants resulting in presenile dementia.