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ERC

IMMUNOALZHEIMER Report Summary

Project ID: 695714
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - IMMUNOALZHEIMER (The role of immune cells in Alzheimer's disease)

Reporting period: 2016-09-01 to 2018-02-28

Summary of the context and overall objectives of the project

"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 project team has recently shown an unexpected role for neutrophils in Alzheimer's disease, supporting the innovative idea that circulating leukocytes contribute to disease pathogenesis.
The MAIN GOAL of IMMUNOALZHEIMER is to study the role of circulating immune cells in animal models of Alzheimer's disease, focusing on neutrophils and T cells. We will study leukocyte-endothelial interactions in CNS microcirculation in intravital microscopy experiments. Leukocyte trafficking will be also studied inside the brain parenchyma by using two-photon microscopy, which will allow us to characterize leukocyte dynamic behaviour and the crosstalk between migrating leukocytes and CNS cells. The effect of therapeutic blockade of leukocyte-dependent inflammation mechanisms will be determined in animal models of Alzheimer's disease. Finally, the presence of neutrophils and T cells will be studied on brain samples from Alzheimer's disease patients and we will correlate leukocyte accumulation and microenvironmental positioning to disease severity.
Overall, IMMUNOALZHEIMER will generate fundamental knowledge to the understanding of the role of immune cells in neurodegeneration and will unveil novel therapeutic strategies to address Alzheimer’s disease.
"

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The MAIN GOAL of our project is to study the role of immune cells in the pathogenesis of animal models of Alzheimer’s disease and to identify novel potential therapeutic targets for this disease.
During the first 18 months, at OBJECTIVE I we characterized neutrophil-driven inflammation and cognitive decline in Alzheimer’s disease. Particularly, we investigated neutrophil accumulation in models of Alzheimer’s disease and characterized the molecular mechanisms controlling neutrophil-endothelial interactions in intravital microscopy studies in brain microcirculation. We also characterized neutrophil intraparenchymal dynamics including the interactions with neural cells and identified the previously unknown existence of cell-cell interactions in animals with Alzheimer’s-like disease. We demonstrated the impact of blockade of trafficking mechanisms on disease and our data showed that therapeutic inhibition of key migration mechanisms improves memory and reduces microglial activation, amyloid deposition and tau hyperphosphorylation (Pietronigro et al., manuscript submitted; Zenaro et al., manuscript in preparation). Finally, at Objective I we started the characterization of neutrophil accumulation in patients with Alzheimer’s disease to correlate disease severity to neutrophil infiltration.
During the first 18 months, at OBJECTIVE II we determined the impact of T cells on cognitive decline and neuropatological changes in mice with Alzheimer’s-like disease. Notably, we found a previously unknown role for specific T cell subpopulations in disease pathogenesis. Moreover, we found that early inhibition of T cell function blocks disease development and improves memory in animal models of Alzheimer’s disease (Ghasemi et al., manuscript in preparation; Iannoto et al., manuscript in preparation). We also characterized the molecular mechanisms controlling the interactions between inflamed brain endothelium and T cells and studied the motility behavior and interactions between T cells and neural cells. We found a role for specific integrins in activated T cell motility inside inflamed central nervous system, suggesting these molecules may represent novel therapeutic targets in Alzheimer’s disease (Dusi et al., manuscript submitted; Rossi et al., manuscript in preparation).
During the first financial reporting period we also characterized the molecular mechanisms controlling T cell trafficking mechanisms in the Alzheimer’s disease brain and the contacts between migrating leukocytes and neural cells. All these microscopy studies, which represent a large part of the project, were initially planned to be performed exclusively in vivo. Indeed, animal models are invaluable to address critical questions regarding the pathogenesis of human diseases and are essential for testing new therapeutic strategies. However, animal models are also very costly, may lack sufficient sensitivity in imaging experiments, are time consuming and present several ethical issues.
In recent years new powerful and groundbreaking approaches have emerged in the context of tissue and organ 3D cultures, coupling co-culture of many cells of different origins to microfluidic devices, allowing the building of increasingly complex in vitro micro environments recapitulating, at least partially, the complexity of in vivo conditions. These 3D cutting-edge approaches, globally called organoids, organ chips or lab on chips, hold the promise to revolutionize bio-medical research having many unquestionable advantages, including a level of complexity reasonably resembling the in vivo counterpart, better standardized and reproducible experimental contexts, higher sensitivity of imaging experiments, possibility to study fine molecular mechanisms under dynamic conditions, opportunity of technological scale up, containment of costs and less ethical issues to address compared to in vivo studies (Pamploni et al., Nat Rev Mol Cell Biol. 2007 Oct;8(10):839-45; Kraehenbuehl e

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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, leukocyte trafficking and neuroinflammation as well as our skills in advanced microscopy and animal models of Alzheimer’s disease place us at the leading edge for the study of the circulating immune cells in this disease. We will also use a cutting-edge 3D system, to provide more insight into the molecular mechanisms responsible for leukocyte-mediated damage in Alzheimer’s disease, facilitating the achievement of project objectives and reducing the number of laboratory animals.
THE IMMUNOALZHEIMER’s team is therefore in the unique position to bring innovative ideas in the field leading to a more comprehensive picture of disease pathogenesis in which the role of immune cells has the potential to take the stage.
Overall the studies proposed in IMMUNOALZHEIMER are pioneering and we expect to identify novel disease mechanisms and potential therapeutic targets in Alzheimer’s disease.
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