Cell-specific expression of APP and GABA_BR1 isoforms in wild-type and the APP NL-G-F mouse model of Alzheimer's...

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 (AD). APP proteolytic processing also generates soluble APP alpha (sAPPα) which modulates synaptic transmission and neurite outgrowth through the γ-aminobutyric acid type B receptor (GABA_BR). sAPPα specifically binds the 1a isoform of GABA_BR subunit 1 (R1a) which contains two sushi domains absent in R1b. Here, we define the cell type-specific expression patterns of APP and GABA_BR1a in the brain and assess their alterations in the APP NL-G-F model of AD. We determined relative RNA levels of R1a and R1b isoforms in oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons in adult mice using two approaches. We developed an isoform-specific RNAseq analysis workflow to probe publicly available datasets. We also isolated these cell types from a single mouse brain and performed RT-qPCR with isoform-specific primers. APP and GABA_BR1 isoforms were differentially expressed among cell types. APP and GABA_BR1a expression were highest in oligodendrocytes. In contrast, GABA_BR1b expression was highest in astrocytes. While microglia expressed relatively low levels of GABA_BR, they showed the greatest change in GABA_BR expression in the APP NL-G-F mouse model, with alterations that were both sex- and age-specific. Together, our findings identify candidate cell types in which future studies may investigate the potential role of APP-GABA_BR signaling in health and AD.