Targeting purinergic signaling in plaque-associated microglia in a mouse model with Alzheimer's disease-like pathology
Matthias Brückner1, Jan N Hansen1,2, Ligang Gu1, Sangyong Lee3, Christa E Müller3,Gabor Petzold2,4 and Annett Halle1,2,4 1Center of Advanced European Studies and Research, Bonn, Germany; 2German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; 3 University of Bonn, Bonn, Germany, 4University Hospital Bonn, Bonn, Germany
Numerous studies have highlighted the importance of microglia in Alzheimer's disease (AD), implicating microglia as a promising target for AD treatment. Microglial cells in mouse models of AD show signs of functional impairment. Whether alterations in purinergic signaling, which under physiological conditions is critically involved in shaping microglial functions, contribute to this phenomenon and whether microglial dysfunction is reversible by targeting purinergic signaling has remained unclear. Dynamics, morphology and phagocytic capacity of microglial cells from APP/PS1-CX3CR1-EGFP mice were assessed using intravital 2-photon microscopy and acute cerebral slice phagocytosis assays. We found a striking difference in microglial functional parameters between plaque-associated and plaque-distant microglia with severe functional impairment in plaque-associated and only minor impairment in plaque-distant cells. Transcriptional analysis of microglial cells harvested by laser-microdissection showed increased expression of purine degrading enzymes and purinoreceptors in plaque-associated cells. Importantly, purinoreceptor agonists or pharmacological blockage of nucleotide-degrading enzymes rapidly normalized phagocytic of plaque-associated microglia in slices from APP/PS1 mice. In summary, we have identified an impairment of cellular dynamics, morphology and phagocytic capacity in plaque-associated microglia in the APP/PS1 mouse model, which was rapidly reversible by modulating purinergic signaling. Thus, targeting microglial purinergic signaling may represent a promising novel approach for the treatment of AD.
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