CONICET | Buscador de Institutos y Recursos Humanos

Astrocytes are nowadays undoubtedly endorsed as key players in CNS functionality and plasticity. We recently showed that Metabotropic Glutamate Receptor 3 (mGlu3R) activation by LY379268 promotes the non-amyloidogenic cleavage of amyloid precursor protein (APP) in cultured astrocytes, leading to increased release of neuroprotective sAPPα (Durand et al., 2014). Furthermore, mGlu3R expression was diminished in hippocampal astrocytes from PDAPP-J20 mice, suggesting a role for these receptors in Alzheimer?s disease. In order to enquire into the implications of astroglial-derived neurotrophins after mGlu3R activation on neurotoxicity triggered by amyloid β (Aβ), cultured hippocampal neurons were incubated with conditioned media from LY379268-treated astrocytes (LY/CM) prior to challenge with Aβ25-35 for 24 h. We found that astrocyte-derived sAPPα is involved in neuroprotection exerted by LY/CM, since its immunodepletion restored neuronal death to control levels. LY379268 also induced BDNF expression in astrocytes, and neutralizing BDNF from LY/CM prevented the neuroprotective effect of the CM on Aβ neurotoxicity. Interestingly, LY379268 was also able to decrease Aβ-induced neuronal death by acting directly on neurons. On the other hand, mGlu3R activation in both astrocytes and microglia increased the rate of Aβ and latex bead uptake, and the reduction in neuronal death when co-culturing with LY379268-pretreated astrocytes may be associated to 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 sAPPα and BDNF, and (ii) it induces amyloid removal from the extracellular space by glial phagocytic mechanisms.