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The role of immune cells in Alzheimer's disease

Periodic Reporting for period 4 - IMMUNOALZHEIMER (The role of immune cells in Alzheimer's disease)

Reporting period: 2021-03-01 to 2022-08-31

Alzheimer’s disease is the most common form of dementia and it affects more than 35 million people worldwide. Based on statistical studies on the aging population, it is estimated that by 2030 nearly 66 million people will have Alzheimer’s disease and by 2050 Alzheimer's will be a global epidemic with rates exceeding 115 million individuals. Alzheimer’s disease drives to death within 3 to 9 years after diagnosis and THERE IS NO CURE FOR THE DISEASE. Current drugs provide symptomatic benefit for up to 1 year, but there are no disease-modifying therapies.
Alzheimer's disease is characterized by a progressive deterioration of cognitive functions, and the neuropathological features include amyloid beta deposition, aggregates of hyperphosphorylated tau protein, and the loss of neurons in the central nervous system (CNS). Research efforts in the past decades have been focused on neurons and other CNS resident cells, but this "neurocentric" view has not resulted in disease-modifying therapies.
Growing evidence suggests that inflammation mechanisms are involved in Alzheimer's disease and the MAIN GOAL of IMMUNOALZHEIMER was to study the role of circulating immune cells, also called leukocytes, in animal models of Alzheimer's disease, focusing on neutrophils and T cells. We studied the interactions between immune cells and leukocyte-endothelial interactions in the CNS microcirculation and leukocyte migration inside the brain parenchyma by using advanced microscopy techniques. We also studied how migrating immune cells affect the phenotype and functionality of neurons and glial cells discovering new pathological cellular interplays in Alzheimer’s disease. The effect of therapeutic blockade of detrimental leukocyte-dependent inflammation mechanisms was assessed in animal models of Alzheimer's disease. Finally, the presence of neutrophils and T cells was studied on brain samples from Alzheimer's disease patients and we correlated leukocyte accumulation to disease severity.
Overall, IMMUNOALZHEIMER generated fundamental knowledge on novel molecular and cellular mechanisms contributing to the development of neurodegeneration and neuroinflammation and unveiled novel therapeutic strategies to address Alzheimer’s disease.
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.
Alzheimer’s disease is the most common form of dementia affecting more than 35 million people worldwide and its prevalence is projected to nearly double every 20 years with tremendous social and economic impact on the society. There is no cure for Alzheimer's disease and current drugs only temporarily improve disease symptoms.
The research activities proposed in IMMUNOALZHEIMER are therefore in the context an important challenge for the society: the Alzheimer's disease global epidemic. Our project goes beyond the state-of-the-art of the amyloid hypothesis and “neurocentric” views in Alzheimer’s disease proposing a role for circulating immune cells in disease pathogenesis.
IMMUNOALZHEIMER is an INTERDISCIPLINARY project based on the innovative idea of a role for circulating leukocytes in AD pathogenesis. Our expertise in immunology, pathology, neuroscience, leukocyte trafficking and neuroinflammation as well as our skills in advanced microscopy and models of Alzheimer’s disease placed us at the leading edge for the study of the circulating immune cells in this disease. We also used cutting-edge in vitro systems to provide more insight into the molecular mechanisms responsible for leukocyte-mediated damage in Alzheimer’s disease, facilitating the achievement of project objectives.
THE IMMUNOALZHEIMER project brought innovative ideas in the field leading to a more comprehensive disease picture and identified novel potential therapeutic targets for Alzheimer’s disease.