Session Title: Alzheimer's Disease (AD) including Non-Cognitive Aspects
Presentation Date: Friday, March 14 – Saturday, March 15, 2009
Aβ PEPTIDE CONFORMATION-DEPENDENT ACTIVATION OF MICROGLIA
T. Heurtaux, A. Michelucci, S. Losciuto, C. Gallotti, P. Felten, E. Morga, P. Heuschling
University of Luxembourg, Laboratory of Neurobiology, Luxembourg, Luxembourg
The most common age-related neurodegenerative disorder, Alzheimer's disease (AD), is characterized by the presence of extracellular deposits referred to as amyloid β (Aβ) complexes or senile plaques. Aβ is first produced as a 4 kDa monomer, but readily aggregates to form multimeric complexes (> 50 kDa). In the brain of AD patients, abundant reactive microglia, the resident central nervous system macrophages, migrate to and surround the Aβ plaques. A wide range of microglial pro-inflammatory mediators is then produced.
In this work, we have investigated the effects of different conformations of Aβ(1-42) peptide on microglial activation. Stimulation of a murine microglial cell line with different Aβ forms induced an inflammatory state, which was peptide conformation-dependent. The inflammatory response is even stronger in primary murine microglia. In both cell types, oligomeric forms induced a higher inflammatory response, whereas the fibrillar conformation appeared to be less harmful (low molecular weight Aβ oligomers > high molecular weight Aβ oligomers > fibrillar Aβ). The use of bocMLF, a formylpeptide receptor FPR2 antagonist, reduced the Aβ-induced inflammatory response. Furthermore, the Aβ-induced signal transduction was found to depend on phosphorylation mechanisms induced by mitogen-activated protein kinases (ERK and JNK, but not p38), and on AP-1/NFkB pathways activation.
These results show that the intensity of the reactive microgliosis, observed during AD, is dependent on the Aβ peptide conformation.