[en] BACKGROUND: An important hallmark of Alzheimer's disease (AD) is the increase of Aβ1-42 burden and its accumulation to senile plaques, leading the reactive gliosis and neurodegeneration. The modulation of glia cell function represents an attractive therapeutic strategy, but is currently limited by an incomplete understanding of its relevance for AD. The chemotactic G-protein coupled formyl peptide receptor (FPR), which is known to modulate Aβ1-42 uptake and signal transduction, might be one candidate molecule regulating glia function in AD. Here, we investigate whether the modulation of FPR exerts beneficial effects in an AD preclinical model.
METHODS: To address this question, APP/PS1 double-transgenic AD mice were treated for 20 weeks with either the pro-inflammatory FPR agonist fMLF, the FPR1/2 antagonist Boc2 or the anti-inflammatory FPR2 agonist Ac2-26. Spatial learning and memory were evaluated using a Morris water maze test. Immunohistological staining, gene expression studies, and flow cytometry analyses were performed to study neuronal loss, gliosis, and Aß-load in the hippocampus and cortex, respectively.
RESULTS: FPR antagonism by Boc2-treatment significantly improved spatial memory performance, reduced neuronal pathology, induced the expression of homeostatic growth factors, and ameliorated microglia, but not astrocyte, reactivity. Furthermore, the elevated levels of amyloid plaques in the hippocampus were reduced by Boc2-treatment, presumably by an induction of amyloid degradation.
CONCLUSIONS: We suggest that the modulation of FPR signaling cascades might be considered as a promising therapeutic approach for alleviating the cognitive deficits associated with early AD. Additional studies are now needed to address the downstream effectors as well as the safety profile of Boc2.
Disciplines :
Neurologie
Auteur, co-auteur :
Schröder, Nicole; Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, D-18057, Rostock, Germany ; Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
Schaffrath, Anja; Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, D-18057, Rostock, Germany ; Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
Welter, Josua A; Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, D-18057, Rostock, Germany ; Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
Putzka, Tim; Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, D-18057, Rostock, Germany ; Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
Griep, Angelika; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Bonn, Germany
Ziegler, Patrick; Institute for Occupational and Social Medicine, RWTH Aachen University, Aachen, Germany
Brandt, Elisa; Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
Samer, Sebastian; Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, D-18057, Rostock, Germany ; Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
HENEKA, Michael ; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Kaddatz, Hannes; Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, D-18057, Rostock, Germany
Zhan, Jiangshan; Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, D-18057, Rostock, Germany
Kipp, Eugenia; Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, D-18057, Rostock, Germany ; Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
Pufe, Thomas; Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
Tauber, Simone C; Department of Neurology, RWTH University Hospital Aachen, Aachen, Germany
Kipp, Markus; Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, D-18057, Rostock, Germany
Brandenburg, Lars-Ove; Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, D-18057, Rostock, Germany. Lars-Ove.Brandenburg@med.uni-rostock.de ; Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany. Lars-Ove.Brandenburg@med.uni-rostock.de
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