Towards an Interleukin-10-producing B cells immunotherapy for Alzheimer's disease. – iBregAD

Alzheimer’s disease (AD) is the most common neurodegenerative disorder associated with dementia, cognitive decline and memory loss. AD is characterized by the pathological formation of intraneuronal aggregates of tau protein and extracellular aggregates of amyloid ß (Aß). The view of the brain as an immune-privileged organ has moved towards a pivotal role of the crosstalk between brain-resident and peripheral immune cells in both physiological and pathological conditions. Hence, better understanding the peripheral-central immune crosstalk is crucial to develop new therapies in neurological conditions. In this line, B cells are found in the brain of AD patients and AD-like mice, although their impact on disease progression remains unclear and their manipulation led to controversial results. As resident immune cells of the central nervous system (CNS), microglia are primarily responsible for phagocytotic clearance of Aß. However, there is an increasing recognition that exacerbated neuroinflammation and dysfunction of microglia play a critical role in AD. Our lab has recently developed an experimental protocol in which B cells are cultured in vitro to become anti-inflammatory. Our preliminary data indicate that these B cells exert potent anti-inflammatory effects in the central nervous system, downregulate microglial AD relevant genes and improve cognitive deficits in AD-like mice. In light of these data, our objectives are i) to deeply characterize the phenotypes and functions of B cells infiltrating the brain of AD-like mice at different disease stages, ii) to test whether such anti-inflammatory B cells can positively impact disease development and/or progression in models of AD-like pathology and iii) to characterize phenotypically and functionally B cells at the periphery along disease progression in AD patients, in order to highlight potential correlations with clinical presentation and disease severity.
The iBregAD project aims to pioneer a novel immunotherapy for AD by harnessing in vitro anti-inflammatory B cells. This innovative approach seeks to modulate neuroinflammation and neurodegeneration, offering a novel approach to disease modification. By influencing CNS environment, anti-inflammatory B cells hold potential in attenuating the neuroinflammatory processes characteristic of AD. Chronic neuroinflammation is widely implicated in AD progression, contributing to neuronal damage and cognitive decline. Through their ability to mitigate neuroinflammation, anti-inflammatory B cells may offer neuroprotective benefits, preserving neuronal integrity and retarding disease advancement. Notably, our project stands out for its originality and ambition in elucidating the intricate interplay between B cells in peripheral and central immune systems. Additionally, it aims to unravel the cellular and molecular mechanisms through which anti-inflammatory B cells orchestrate CNS inflammatory remodeling during AD progression. This deeper understanding not only enhances our comprehension of the disease but also holds promise for identifying novel biomarkers crucial for advancing therapeutic interventions, ultimately enhancing the quality of life for patients.