Inhibition of formyl peptide receptors improves the outcome in a mouse model of Alzheimer disease

Journal of Neuroinflammation

Thomas Pufe¹  Elisa Brandt¹  Michael T. Heneka²  Angelika Griep²  Simone C. Tauber³  Patrick Ziegler⁴  Anja Schaffrath⁵  Josua A. Welter⁵  Markus Kipp⁵  Sebastian Samer⁵  Lars-Ove Brandenburg⁵  Eugenia Kipp⁵  Jiangshan Zhan⁵  Hannes Kaddatz⁵  Nicole Schröder⁵  Tim Putzka⁵ 

[1] Department of Anatomy and Cell Biology, RWTH Aachen University;Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn;Department of Neurology, RWTH University Hospital Aachen;Institute for Occupational and Social Medicine, RWTH Aachen University;Institute of Anatomy, Rostock University Medical Center;

关键词: Alzheimer disease;    Amyloid beta;    Formyl peptide receptor;    Glia cell;    Microglia;    Innate immunity;   

DOI  :  10.1186/s12974-020-01816-2

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown