Microglial Activation and Differentiation : Analysis of Signal Transduction and Phenotype Acquisition - GLIA2

Coordinating Institution: Université du Luxembourg
Contracting Partner(s): CRP Gabriel Lippmann , CRP-Santé
From: 01/02/2007
To: 31/01/2009
Budget: 383,000.00€
Contact(s): Heuschling Paul

Summary

Reactive microglia migrate to and surround the Ab plaques in Alzheimer’s disease. In this work, we investigated the effects of different conformations of Ab(1‑42) peptide on microglial activation. Stimulation of murine microglial cells with different Ab forms induced an inflammatory state, which was peptide conformation-dependent. The light oligomeric forms (L-Abol) induced a higher inflammatory response, whereas the fibrillar conformation appeared to be less potent. The presence of interferon-g potentiated the Ab‑induced inflammatory response.

A large number of glial cell surface receptors are known to mediate interaction with the Ab peptide. Microglial cells express notably formylpeptide receptor (FPR). We have shown an Ab-conformation dependent FPR2 overexpression in microglial cells.To establish the mechanism by which Ab induces a pro-inflammatory state, a single dose of L-Abol, the most potent peptide conformation, is used. First, we show that the inhibition of the FPR2 receptor, by the use of the bocMLF antagonist, down-regulates the expression of numerous pro-inflammatory genes induced by L-Abol in microglial cells.

Moreover, mitogen activated protein kinases (MAPK) subfamilies are implicated in this Ab-induced inflammatory state. The use of MAPK inhibitors shows that ERK and JNK MAPK are both implicated in this mechanism in microglial cell line MMGT12. We show that in primary microglia, p38, ERK and JNK MAPK are all implicated in the Ab-induced microglial activation.In the present study, the Ab-induced microgliosis is associated with the recruitment of the AP-1 transcription factor. Activated AP-1 complex is composed of c-Jun homodimer in both microglial cell types. The phosphorylation of the c-Jun subunit appears to be Ab-conformation-dependent but also IFNg-dependent in microglial cells.

The L-Abol also increases the phosphorylation of c-Jun. In addition, the blocking of the FPR2 receptor decreases the AP-1 activation. To our knowledge, it is the first time that the FPR2 receptor is shown to be associated with the activation of the AP-1 factor. In our conditions, an Ab exposure also induces the NFkB recruitment in microglial cells. This NFkB activation is strongly decreased after a bocMLF pretreatment.

Thus, these results present further evidence of a possible link between FPR2, MAPK, NFkB, AP‑1 and inflammatory microglial response.To complete these results, a microarray-based transcription profile study, a proteomic investigation and in vivo experiments (Alzheimer strain mouse) are currently being carried out.

Refereed Scientific Publications

• Michelucci A, Heurtaux T, Grandbarbe L, Morga E and Heuschling P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-b(Journal of Neuroimmunology (2009), 210, 3-12)