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 sAPPα. 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 β (Aβ). Conditioned medium from LY379268-treated astrocytes protected hippocampal neurons from Aβ-induced cell death. Immunodepletion of sAPPα 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 Aβ neurotoxicity. LY379268 was also able to decrease Aβ-induced neuron death by acting directly on neuronal mGlu3R.
On the other hand, LY379268 increased Aβ uptake in astrocytes and microglia. Indeed, and more importantly, a reduction in Aβ-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 Aβ neurotoxicity: (i) it increases the release of protective neurotrophins such as sAPPα and BDNF, and (ii) it induces amyloid removal from extracellular space by glia-mediated phagocytosis.