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

DURAND, DANIELA; CARNIGLIA, LILA; TURATI, JUAN; RAMÍREZ, DELIA; SABA, JULIETA; CARUSO, CARLA; LASAGA, MERCEDES

NEUROPHARMACOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2017

0028-3908

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