Microglial phagocytosis and purinergic signaling in Alzheimer’s disease

Microglia, the primary immune cells of the central nervous system, interact through multiple physiological functions with processes in the healthy as well as diseased brain parenchyma. As a cellular link between the immune system and the central nervous system, microglia monitor their environment by using their ramified processes to eventually eliminate harmful exogenous and endogenous waste, pathogens or cell debris through phagocytosis. In the neurodegenerative Alzheimer's disease, microglia change the activation status from a ramified to an amoeboid-activated phenotype and accumulate around amyloid beta plaques. Recent studies show a physiological change in the microglial functions in the Alzheimer mouse model, which manifests itself in the reduction of microglial phagocytosis. Our research presents a link between diminished microglial phagocytosis activity in an Alzheimer mouse model and disruption of purinergic microglial receptor signaling. The measurement of phagocytosis activity by particle uptake after P2Y6 purinergic receptor activation could be stimulated in young 3- to 4-month old healthy control animals as well as in 5xFAD-transgenic Alzheimer's animals, a mouse model of amyloid-beta-plaque deposition. However, this P2Y6R-mediated potentiation of phagocytic activity is reduced in plaque-associated microglia of older 9 to 11-month-old 5xFAD mice. This impairment of phagocytosis activation by the P2Y6-mediated purinergic signaling pathways is thus not congenital and only develops in later stages of amyloidosis of the 5xFAD Alzheimer mouse model. Furthermore, we show that uridine diphosphate, a P2Y6 receptor ligand, induces electrophysiological microglia membrane currents that are altered in response and amplitude in microglia in close regional association with plaques, but not in plaque-free regions of 5xFAD animals. These changes were accompanied by changes in membrane properties and potassium channel activity of plaque-associated microglia in early and late stages of amyloidosis. Thus, our research results show both a change in the phagocytic activity and the electrophysiological properties of the plaque-associated microglia of the 5xFAD Alzheimer mouse in the context of purinergic signaling.