Oligodendrocytes show enriched expression of amyloid precursor protein and GABA B receptor isoform 1a

Amyloid precursor protein (APP) is a type I transmembrane protein that undergoes proteolytic processing to generate amyloid-β, the main component of amyloid plaques found in brains with Alzheimer's disease. The proteolytic processing of APP also generates soluble APP alpha (sAPPα) which can modulate synaptic transmission and neurite outgrowth through the γ-aminobutyric acid type B receptor (GABA_BR). Whether GABA_BR mediates functions of sAPPα in other neural cell types such as glia remains unknown. sAPPα binds the R1a subunit isoform of GABA_BR1 which contains two sushi domains absent in R1b. It is unclear whether both GABA_BR1 isoforms are expressed equally across brain cell types. We determined relative RNA levels of the GABA_BR1a and 1b isoforms in oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons in adult mice using two approaches. We developed a GABA_BR1 isoform-specific RNAseq analysis workflow to probe a publicly available dataset. We also isolated five cell types from a single mouse brain and performed RT-qPCR. We show that the GABA_BR1a and 1b isoforms are differentially expressed among cell types. GABA_BR1a expression was highest in oligodendrocytes and GABA_BR1b expression was highest in astrocytes, suggesting that sAPPα-mediated GABA_BR signaling may be most prominent in oligodendrocytes. We also confirmed that APP is expressed in all five cell types and showed that APP RNA levels are highest in oligodendrocytes. Together, our findings uncover cell type-specific expression of GABA_BR isoforms and highlight oligodendrocytes as a principal cell type for GABA_BR1a-mediated APP signaling, providing a foundation for future mechanistic studies.