Trained Immunity in Neurodegenerative Diseases

Abstract Alzheimer’s disease (AD) and Parkinson’s disease (PD) are complex and progressive neurodegenerative disturbances leading to cognitive or motor dysfunctions and lacking effective therapy. A deregulation of innate immune response and inflammation appears to be deeply involved in both illnesses, though with still unclear mechanisms. Evidence in animals attributes a neurodegeneration-modulating role to mechanisms of innate memory, but human data on this topic are still scarce. In this study, we investigated whether -possibly due to concomitant factors including enhanced infectious burden, microbial dysbiosis and genetic risk factors linked to immunity-the innate immune cells of AD and PD patients show long-term functional reprogramming characterized by either potentiated or tolerant responses, which could ultimately contribute to disease development. Thus, following repeated in vitro stimulation with either heat-inactivated Candida albicans or LPS, we measured the cytokine response of CD14+ cells from AD and PD patients, both in comparison with those of age- and gender-matched healthy control subjects and in association with symptom severity. We observed different cytokine patterns associated with tolerant or potentiated responses among the three groups of subjects, pointing to different and disease-dependent trained immune status in patients. Our results would provide insights about how previous triggering of innate immunity can influence neuroinflammation and disease progression, offering new knowledge on trained immunity impact in neurodegenerative diseases.