PMID- 28495373 OWN - NLM STAT- MEDLINE DCOM- 20180417 LR - 20180417 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 123 DP - 2017 Sep 1 TI - Amyloid-beta neurotoxicity and clearance are both regulated by glial group II metabotropic glutamate receptors. PG - 274-286 LID - S0028-3908(17)30204-6 [pii] LID - 10.1016/j.neuropharm.2017.05.008 [doi] AB - 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 sAPPalpha. 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 (Abeta). Conditioned medium from LY379268-treated astrocytes protected hippocampal neurons from Abeta-induced cell death. Immunodepletion of sAPPalpha 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 Abeta neurotoxicity. LY379268 was also able to decrease Abeta-induced neuron death by acting directly on neuronal mGlu3R. On the other hand, LY379268 increased Abeta uptake in astrocytes and microglia. Indeed, and more importantly, a reduction in Abeta-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 Abeta neurotoxicity: (i) it increases the release of protective neurotrophins such as sAPPalpha and BDNF, and (ii) it induces amyloid removal from extracellular space by glia-mediated phagocytosis. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Durand, Daniela AU - Durand D AD - INBIOMED Instituto de Investigaciones Biomedicas UBA-CONICET, Facultad de Medicina, UBA, Ciudad Autonoma de Buenos Aires, 1121 ABG, Argentina. Electronic address: ddurand@fmed.uba.ar. FAU - Carniglia, Lila AU - Carniglia L AD - INBIOMED Instituto de Investigaciones Biomedicas UBA-CONICET, Facultad de Medicina, UBA, Ciudad Autonoma de Buenos Aires, 1121 ABG, Argentina. Electronic address: lcarniglia@fmed.uba.ar. FAU - Turati, Juan AU - Turati J AD - INBIOMED Instituto de Investigaciones Biomedicas UBA-CONICET, Facultad de Medicina, UBA, Ciudad Autonoma de Buenos Aires, 1121 ABG, Argentina. Electronic address: jturati@fmed.uba.ar. FAU - Ramirez, Delia AU - Ramirez D AD - INBIOMED Instituto de Investigaciones Biomedicas UBA-CONICET, Facultad de Medicina, UBA, Ciudad Autonoma de Buenos Aires, 1121 ABG, Argentina. Electronic address: dramirez@fmed.uba.ar. FAU - Saba, Julieta AU - Saba J AD - INBIOMED Instituto de Investigaciones Biomedicas UBA-CONICET, Facultad de Medicina, UBA, Ciudad Autonoma de Buenos Aires, 1121 ABG, Argentina. Electronic address: juli_saba@hotmail.com. FAU - Caruso, Carla AU - Caruso C AD - INBIOMED Instituto de Investigaciones Biomedicas UBA-CONICET, Facultad de Medicina, UBA, Ciudad Autonoma de Buenos Aires, 1121 ABG, Argentina. Electronic address: ccaruso@fmed.uba.ar. FAU - Lasaga, Mercedes AU - Lasaga M AD - INBIOMED Instituto de Investigaciones Biomedicas UBA-CONICET, Facultad de Medicina, UBA, Ciudad Autonoma de Buenos Aires, 1121 ABG, Argentina. Electronic address: mlasaga@fmed.uba.ar. LA - eng PT - Journal Article DEP - 20170508 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Amino Acids) RN - 0 (Amyloid beta-Peptides) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Bridged Bicyclo Compounds, Heterocyclic) RN - 0 (Culture Media, Conditioned) RN - 0 (Excitatory Amino Acid Agonists) RN - 0 (LY 379268) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, Metabotropic Glutamate) RN - 0 (metabotropic glutamate receptor 3) SB - IM MH - Amino Acids/pharmacology MH - Amyloid beta-Peptides/*metabolism MH - Animals MH - Astrocytes/drug effects/*metabolism/pathology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Bridged Bicyclo Compounds, Heterocyclic/pharmacology MH - Cell Death/drug effects/physiology MH - Coculture Techniques MH - Culture Media, Conditioned MH - Excitatory Amino Acid Agonists/pharmacology MH - Hippocampus/drug effects/metabolism/pathology MH - Microglia/drug effects/*metabolism/pathology MH - Neurons/drug effects/metabolism/pathology MH - Neuroprotection/drug effects/physiology MH - Neuroprotective Agents/pharmacology MH - Phagocytosis/drug effects/physiology MH - Rats, Wistar MH - Receptors, Metabotropic Glutamate/agonists/*metabolism OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid beta clearance OT - BDNF OT - Metabotropic glutamate receptors OT - Neuron-glia interaction OT - sAPPalpha EDAT- 2017/05/13 06:00 MHDA- 2018/04/18 06:00 CRDT- 2017/05/13 06:00 PHST- 2017/01/31 00:00 [received] PHST- 2017/05/05 00:00 [revised] PHST- 2017/05/07 00:00 [accepted] PHST- 2017/05/13 06:00 [pubmed] PHST- 2018/04/18 06:00 [medline] PHST- 2017/05/13 06:00 [entrez] AID - S0028-3908(17)30204-6 [pii] AID - 10.1016/j.neuropharm.2017.05.008 [doi] PST - ppublish SO - Neuropharmacology. 2017 Sep 1;123:274-286. doi: 10.1016/j.neuropharm.2017.05.008. Epub 2017 May 8.