The immune system plays a pivotal role in homeostasis and its alterations influence the incidence and severity of neurodegenerative diseases; however, we are only beginning to understand the full scale of this effect. We know that immune cells change during ageing, however, we still do not know how these changes predispose us or protect us from neurodegeneration.
Our lab aims to understand how immune cells change with age and how this affects neurodegenerative diseases such as Alzheimer’s. As we discover new pathways and molecules important for immune regulation in ageing, we strive to identify new potential therapeutic targets. Specifically, we are interested in understanding the function of the voltage-gated proton channel HVCN1 in immune responses, as well as signalling pathways that regulate inflammation in microglia (summary in Fig. 1).
The voltage-gated proton channel HVCN1 in immune responses
There is only one mammalian voltage-gated proton channel, HVCN1. It works to relieve intracellular acidification and membrane depolarization, letting protons out of the cell following their chemical gradient. In doing so, it sustains the production of reactive oxygen species (ROS) by the enzyme NADPH oxidase (Fig. 2). We were the first to describe HVCN1 role in regulating B cell responses (Capasso et al, Nat Immunol, 2010). HVCN1 loss causes a strong impairment of antibody responses, due to reduced B Cell Receptor signaling. This is due to diminished ROS production by the NADPH oxidase: fewer ROS mean they are no longer able to oxidase and therefore inhibit phosphatases involved in B Cell Receptor signalling. We have also described a splicing variant of HVCN1, shorter at the N-terminus, which is able to mediate larger currents and it is upregulated in B cell malignancies such as Chronic Lymphocytic Leukaemia (Hondares et al., PNAS, 2014). We continue to study HVCN1 role in CLL in the lab in London, whereas we concentrate on HVCN1 in myeloid cells and its potential role in Alzheimer’s disease here at DZNE Bonn.
Signaling pathways regulating inflammation in aged microglia
Microglia are the immune cells of the brain that play important roles in neuronal cells homeostasis but also contribute to disease pathology in neurodegenerative diseases. We study microglia to establish signalling pathways that regulate their inflammatory responses and how they change with age. In particular, we are currently investigating alterations in the mTOR pathway in aged microglia and how this affects microglia inflammatory responses.