The MAIN GOAL of our interdisciplinary project was to study the role of circulating immune cells in the pathogenesis of Alzheimer’s disease (AD) focusing on neutrophils and T cells.
We studied neutrophil-driven inflammation and cognitive decline in experimental models of AD and identified how neutrophils may damage brain cells. Also, our data showed that pharmacological targeting of neutrophil pro-inflammatory molecules protected neurons from neutrophil-mediated dysfunction, suggesting that inhibition of specific neutrophil pathways may represent a novel therapeutic approach in AD (data presented to several meetings). Based on these innovative data, we obtained a European Research Council (ERC) PROOF OF CONCEPT (POC) project to determine the technical and commercial feasibility of inhibitors targeting specific neutrophil molecules.
Using advanced microscopy, we identified the molecules controlling the adhesion of neutrophils inside blood vessels of the brain and meninges and unveiled the role of previously unknown molecules in this process. We also studied how neutrophils move inside the central nervous system (CNS) and establish cell-cell contacts with neurons and glial cells (data presented to several meetings). Computational biology approaches, including network analysis, and machine learning were used to more deeply analyze and model our data and the results were shown at prestigious congresses in the field.
The study on the role of neutrophils was completed by data strongly suggesting that neutrophils also contribute to disease severity in humans. Particularly, by using high resolution microscopy, we obtained novel data showing the presence of vascular alterations, neutrophil adhesion mechanisms and release of potentially harmful molecules in the brain tissues of patients with AD.
In this project we also studied the role of T cells in models of AD and obtained data showing that these leukocytes were more activated in AD compared to control conditions. We obtained new original data showing a profound alteration of the T cell compartment potentially amplifying AD pathology. Our data also suggest that the blockade of specific T cell molecules inducing neurotoxicity represents a novel therapeutic strategy to protect neurons and alleviate the disease (data presented to meetings; one team member won a prestigious prize from the Italian Neuroimmunology association in 2019). Moreover, we also obtained data showing how T cells and neutrophils collaborate to promote neuroinflammation and brain damage in AD. As determined for neutrophils, we also identified new molecules responsible for the intravascular adhesion and migration inside the CNS of T cells, promoting disease development. The analysis of post-mortem samples led to the obtainment of highly relevant clinical data suggesting that peripheral T cells contribute to brain damage in AD.
Overall, the data obtained during the development of the IMMUNOALZHEIMER project point to circulating leukocytes as central players in the induction of chronic neuroinflammation and neurodegeneration and show novel disease mechanisms and potential therapeutic targets in AD.
