Meningeal Regulatory T-Cells (Tregs) in Individuals with Versus without Alzheimer’s Disease

There is increasing evidence that an anomalous immune response is an important component of Alzheimer’s Disease (AD). The cells that regulate most types of immune reactions are regulatory T cells (a.k.a. Tregs), which are currently being explored in several therapeutic contexts. Recently, we found that a membranous structure encasing the mouse brain, called the meninges, hosts a small but potent Treg population that inhibits the activation of local immune cells, including their production of the inflammatory mediator interferon-γ, thereby blocking their entry into the brain proper. Removal of Tregs results in unrestrained interferon-γ production, immune cell invasion of the brain, death of neural stem cells, and poor spatial memory. Since this scenario is highly reminiscent of that which unfolds in mouse models of AD, it seems imperative to examine the analogous Treg population in humans and, especially, to compare it in individuals that do or do not have AD. Thus, we propose to perform a two-part study, taking advantage of a remarkable collection of autopsy samples to be provided by collaborating with neuropathologists at Massachusetts General Hospital. First, to get a view of the general landscape, we will perform a broad “all comers” survey of the meningeal immune system of 30 autopsy subjects (a mix of individuals with AD, other neurodegenerative diseases, or no evident brain disease), examining all the major cell types and states by quantification of the expression of characteristic proteins. Second, to focus on the key question, we will compare the meningeal Treg compartments of 18 individuals with and 18 without AD, employing single-cell RNA sequencing. Results from these studies will tell us whether humans have a meningeal Treg population analogous to the one we discovered in mice, whether that population is somehow different in individuals with AD, and what features of these Tregs might be impaired. This information would be the first step in harnessing Tregs or their products to impede the progression of AD.