Parkinson’s disease (PD) is primarily driven by the aggregation of alpha-synuclein, which leads to the progressive loss of dopaminergic neurons in the substantia nigra. Beyond this, recent studies have highlighted the involvement of the immune system, particularly innate memory (IM), in modulating disease progression. IM is an adaptive feature of innate immunity that enhances cellular responses to repeated stimuli. While it can confer protection, its dysregulation may promote chronic inflammation and neurodegeneration.
This project aims to investigate IM responses in the early stages of PD by examining the functional reprogramming of innate immune cells following in vitro priming and repeated stimulation. It will also assess each patient’s infectious burden, including exposure to common pathogens such as SARS-CoV-2, and relate these findings to plasma markers of inflammation and neurodegeneration. In parallel, functional, transcriptomic, metabolic, and morphological changes will be studied in healthy and patient-derived microglia-like cells (iMGL) exposed to PD-relevant stimuli, such as alpha-synuclein adducts. The impact of these challenged iMGL on iPSC-derived neurons, and their interactions with peripheral innate immune cells, will also be evaluated.
Finally, the project will explore how individual immune responses relate to cognitive, neuropsychiatric, neuroimaging, and omics data in PD patients. By tracking clinical progression over two years, we aim to identify immune signatures that can predict disease trajectories and support the development of a model for early risk stratification.