Microglial Activation and Differentiation : Balance between Proinflammatory Secretions and Beta-amyloid Clearance

Coordinating Institution: Université du Luxembourg
From: 01/11/2004
To: 31/10/2005
Budget: 188,000.00€
Contact(s): Heuschling Paul

Summary

The amyloid-beta (Aß) cascade hypothesis is the dominant explanation for the pathogenesis of Alzheimer’s disease (AD). Producing the well-known plaques, these Aß peptides accumulate inside the brain tissue causingneuronal degeneration and local inflammatory stress. We need a more complete understanding of the signalling pathways leading to the inefficient clearance of Aß by microglia, the brain-resident macrophage-like cell, as well as to the development of the concomitant pro-inflammatory and thus neurotoxic reaction by the same cells.

The aim of this project was to develop experimental strategies allowing us to influence the balance between pro-inflammatory reactions and Aß clearance. Microgliocytes belong to the monocyte/macrophage cell lineage. Recent findings have shown that, during activation, macrophages differentiate along a continuous spectrum of phenotypes. The extremes of this spectrum are pro-inflammatory cells (M1) on one side and anti-inflammatory cells (M2) on the other. Tentative signature expression profiles and behaviour for these phenotypes have been
presented in the literature.

Based on these findings, we analysed the transcription profiles, the protein expressions and the phagocytic activity of Aß-activated microglial cells. Gene-transcription profiles were established using RT-PCR, real-time quantitative PCR and whole genome microarrays.

Morphological changes, production of free radicals and phagocytic activity were assessed. The preliminary results clearly indicated that Aß-stimulated microglial cells differentiate towards a M1-polarised activated phenotype (pro-inflammatory phenotype): the cytokine and chemokine expression profiles are pro-inflammatory, free radical production is high and the phagocytic activity strongly reduced.

This in vitro behaviour seems to parallel in vivo observations and explains some of the neurotoxic effects observed during AD.

Our results also give some indications that the differentiation of the activated microglial cells can be influenced. Exposure of the cells to the cytokine M-CSF decreases the production of some of the pro-inflammatory cytokines as well as the free radicals.

Treatment of microglial cells with soluble ligands of the Notch pathway has the same effect and also increases their phagocytic activity.

Special attention was given to a set of compounds, protected by patents co-owned by the University of Luxembourg, the University Louis Pasteur and the CNRS. When present during activation, these molecules seem to modulate the differentiation process of microglial cells.

Thus, the project aimed to define scientific and therapeutic strategies against the Aß cascade.