A combined in vitro and in silico analysis of microglia activation to assess the potential of the voltage-gated proton channel HVCN1 as a therapeutic target in Alzheimer’s disease
Microglia are brain resident macrophages and involved in maintenance of the healthy brain, as well as the development of diseases such as Alzheimer’s disease (AD). Microglia express different types of ion channels, including proton channels (e.g. HVCN1), which play a critical role in cellular homeostatic and effector functions. Proton channels act as regulators of cytoplasmic proton concentration (intracellular pH) by removing protons from the cytoplasm of depolarized cells in a voltage-dependent fashion. The role of proton channels in microglia signaling and function is not known. However, reports in the literature suggest its inhibition might limit production of reactive oxygen species and inflammation. By employing a electrophysiological mathematical model based on single transmembrane protein characteristics, we are aiming to study the electrophysiological properties of microglia in different cellular states, with a particular focus on proton channels as a point of intervention and potential therapeutic target in neuroinflammation.
We constructed a comprehensive electrophysiological model for microglia and pooled different patch-clamp recordings available in the literature to characterize the proton channel openings by ODEs and parameter fitting techniques. We based our electrophysiology model on single transmembrane protein characteristics, enabling quantification of the link between cellular states (characterized by varying channel expression level) and electrophysiology.
Melania Capasso (DZNE), Boris Musset (Universität Nürnberg)
- Systems Immunology- Prof. Dr. Michael Meyer-Hermann