Scientists elucidating the mechanisms of the R47H Trem2 variant discover they cannot be replicated in humans
Currently, 5.7 million Americans are living with Alzheimer’s disease (AD), a number that is expected to rise to approximately 14 million by 2050. This strongly begs the need to understand the underlying factors of this disease so that our society can press towards a cure.
Until now, scientists have studied several AD disease variants including Apo lipoprotein E (ApoE) ε4 allele. However, the R47H Trem2 variant, which has been shown to increase the risk of late onset AD, remains largely uncharacterized. TREM2 (triggering receptor expressed on myeloid cells 2) can play both a detrimental and protective role in the regulation of microgliosis, a cellular response to CNS injury.
Researchers at the Ludwig Maximilian University of Munich and German Center for Neurodegenerative Diseases created two mouse models exhibiting the phenotypes of the R47H Trem2 variant, which resulted in a loss of protein function. Trem2 knockout mouse models with the R47H variant overexpressed or knocked in via CRISPR/Cas technology both exhibited reduced mRNA and protein expression. This was due to aberrant splicing of exon 2, which results in the formation of a premature stop codon. However, this phenotype could not be replicated in human iPSC-derived microglia-like cells, emphasizing the need to develop a model more specific to humans.
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Written by Angela
Scientific Support Specialist, Lonza Pharma-Bioscience Solutions at Lonza
