Alzheimer’s and inflammation: exploring the interplay between immune cells in the peripheral immune system and the central nervous system through single-cell RNA-seq

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia and the sixth leading cause of death globally (Haque & Levey, 2019; World Health Organization, 2017). Increases in ageing populations are exacerbating the problem and by 2050 the number of people with a dementia diagnosis is predicted to reach 132 million (World Health Organization, 2017). This will have a significant social and economic cost, however despite the active and growing field of research that has arisen to tackle this problem AD remains a disease with no curative treatment and relatively limited options for management (Revi, 2020). Diagnosis is also challenging, as pre-mortem diagnosis struggles to definitively distinguish AD from other types of dementia with similar presentation and the long prodromal phase in AD can mean that detection is only possible after neuronal damage has already begun (Jack Jr et al., 2018). <br /> The impact of inflammation both in the central nervous system (CNS) and peripheral immune system (PIS) has recently become a highly discussed area of research in the field and advances in our understanding of immune privilege have led to new opportunities to interrogate AD pathogenesis. We now know that systemic inflammation can play a role in the progression of CNS pathologies. Studies have demonstrated that peripheral immune stimuli can trigger long-term immune training in the CNS and worsen the Amyloid-ß (Aß) burden in AD (Wendeln et al., 2018). When we consider this alongside evidence that these peripheral inflammatory events have an impact in the CNS far earlier than previously thought (Jack Jr et al., 2018) then it is clear that elucidating this early stage relationship could be critical to the development of effective interventions. Our study aims to investigate the interplay between AD and peripheral inflammation through analysis of single-cell RNA sequencing (scRNA-seq) data of circulating immune cells in both the CNS and PIS. We sought to identify changes at transcriptional and cellular level between the two systems in parallel by profiling peripheral blood mononuclear cells (PBMCs) from the PIS and immune cells isolated from cerebrospinal fluid (CSF). The study cohort recruited donors via the existing DELCODE, DESCRIBE and DANCER studies at DZNE and used clinical biomarkers to classify these donors using the AT(N) diagnostic framework (Jack Jr et al., 2018). <br /> In my thesis, I identified changes in the CSF myeloid cell compartment of AD donors which suggested inflammation-triggered recruitment from the PIS into the CSF. This was in line with previous observations reporting transitioning of blood-borne myeloid progenitors into a microglia-like myeloid subtype in other neuroinflammatory pathologies (Esaulova et al., 2020). I also identified a separate subset of apparently dysfunctional CSF-specific microglia that were strongly linked to iron metabolism which is known to be dysfunctional in AD (Kenkhuis et al., 2021). No statistically verifiable transcriptional or cellular level changes were identified in the PBMC compartment of AD donors compared to healthy donors. However, this does not rule out that further studies of the PBMC compartment in the early and prodromal phases of AD could generate valuable insights. <br /> Taken together, this work suggests that using scRNA-seq to decipher the transcriptional profiles of peripheral blood and CSF immune cells in AD offers a unique perspective on the progression and pathogenesis of this disease. Characterising the immune landscape in both systems throughout the course of disease may hold the key to identify new biomarkers and develop potential future therapies targeting the peripheral immune system.