Role of peripheral inflammation in driving central nervous system inflammatory signature in pathogenesis of Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) impacts an estimated 6.5 million people in the United States, however, it cannot yet be prevented, slowed or cured. Although the sporadic AD form comprises around 95% of cases, animal models of familial AD are the ones used for basic and translational research. Most of these models are based on human mutations that cause amyloid‐β (Aβ) pathological accumulation. However, the failure of the majority of Aβ‐related clinical trials, has begged the necessity of an alternative approach to address AD. Interestingly, most of the genetic and non‐genetic risk factors for developing sporadic AD are associated with inflammation. Thus, it has been suggested that microglia, the immune cells in the central nervous system, play a key role in the pathogenesis of AD, and that people with systemic inflammatory diseases have a higher incidence of developing AD. In this context, we hypothesize that a specific subset of cells in peripheral blood contributes to AD development through its communication with microglial cells in the brain parenchyma.MethodTo address this hypothesis, we analyzed peripheral blood mononuclear cells (PBMCs) from sex‐ and age‐matched healthy and AD subjects using mass cytometry (CyTOF) and cellular indexing of transcriptomes and epitopes by sequencing (CITE‐seq) technologies. Moreover, we used in vitro and histological approaches to study interactions between PBMCs and human microglial cells.ResultOur preliminary data show a different proportion of peripheral blood immune cell types between healthy controls and AD patients. Remarkably, a specific inflammatory subset of immune cells characterized by the upregulation of pro‐inflammatory signaling pathways and cytokines was detected in blood of AD patients. In addition, T cells in contact with microglia were detected in the parenchyma of AD brains by histological analysis, suggesting adrive of microglial cells towards an inflammatory phenotype that could contribute to AD pathology. We corroborated the pathogenic component of AD blood as healthy PBMCs developed an inflammatory phenotype after stimulation with AD plasma.ConclusionTogether, our data demonstrate the importance of peripheral immune cells in AD disease and reinforce that studying AD as a multifactorial disease could be key to its prevention and treatment.