Altered Membrane Protein Abundance in the Cerebral Cortex of the JNPL3 Mouse Model of Tauopathy

Abstract Developing effective therapeutic approaches for tau-associated neurodegenerative diseases, including frontotemporal dementia and Alzheimer’s disease, remains extremely challenging due to their complex pathogeneses. Membrane proteins constitute a large proportion of current therapeutic and drug delivery targets because of their key roles in essential cellular processes. Here, we examined alterations in membrane protein abundances in the prefrontal cortex of male and female mouse models of human tauopathy, JNPL3 mice, compared with sex-matched wild-type (WT) mice using quantitative proteomics. The data-independent acquisition (DIA) proteomics analysis revealed various alterations in membrane proteins involved in different altered pathways in male JNPL3 mice (e.g., nucleotide metabolism and translation) and female JNPL3 mice (e.g., mitochondrial function). In addition, we found sex-associated changes in the abundances of several proteins previously reported to be involved in tau pathology, such as Reelin, DARPP-32, Zyxin, Tbce, and Gng5, in JNPL3 mice. Our multiple-reaction monitoring absolute quantitative analysis of transporter proteins revealed reduced abundance of the main drug efflux transporter ABCB1 in male JNPL3 mice compared with WT animals, with no changes in female groups. All in all, we provide novel information on membrane proteomic changes in male and female mouse models of human tauopathy, JNPL3 mice, which could aid in developing treatments for tau-associated neurodegenerative diseases and facilitate the prediction of neuropharmacokinetics in female and male patients.