Amyloid-beta neurotoxicity and clearance are both regulated by glial group II metabotropic glutamate receptors

Astrocytes are now fully endorsed as key players in CNS functionality and plasticity. We recently showed that metabotropic glutamate receptor 3 (mGlu3R) activation by LY379268 promotes non-amyloidogenic cleavage of amyloid precursor protein (APP) in cultured astrocytes, leading to increased release of neuroprotective sAPP alpha. Furthermore, mGlu3R expression is reduced in hippocampal astrocytes from PDAPP-J20 mice, suggesting a role for these receptors in Alzheimer's disease. The present study enquires into the role of astroglial-derived neurotrophins induced by mGlu3R activation in neurotoxicity triggered by amyloid beta (A(beta). Conditioned medium from LY379268-treated astrocytes protected hippocampal neurons from A beta-induced cell death. Immunodepletion of sAPP alpha from the conditioned medium prevented its protective effect. LY379268 induced brain-derived neurotrophic factor (BDNF) expression in astrocytes, and neutralizing BDNF from conditioned medium also prevented its neuroprotective effect on A beta neurotoxicity. LY379268 was also able to decrease A beta-induced neuron death by acting directly on neuronal mGlu3R. On the other hand, LY379268 increased A beta uptake in astrocytes and microglia. Indeed, and more importantly, a reduction in A beta-induced neuron death was observed when co-cultured with LY379268-pretreated astrocytes, suggesting a link between neuroprotection and increased glial phagocytic activity. Altogether, these results indicate a double function for glial mGlu3R activation against A beta neurotoxicity: (i) it increases the release of protective neurotrophins such as sAPP alpha and BDNF, and (ii) it induces amyloid removal from extracellular space by glia-mediated phagocytosis. (C) 2017 Elsevier Ltd. All rights reserved.