Amyloid-beta neurotoxicity and clearance are both regulated by glial group II metabotropic glutamate receptors. (1st September 2017)

• Record Type: Journal Article
• Authors: Durand, Daniela; Carniglia, Lila; Turati, Juan; Ramírez, Delia; Saba, Julieta; Caruso, Carla; Lasaga, Mercedes
• Is Part Of: Neuropharmacology. Volume 123(2017)
• Page Start: 274
• Page End: 286
• Publication Date: 2017-09-01
• Subjects: Metabotropic glutamate receptors -- Alzheimer's disease -- Neuron-glia interaction -- Amyloid β clearance -- sAPPα -- BDNF; mGluR metabotropic glutamate receptor -- AD Alzheimer's disease -- Aβ amyloid β -- sAPPα soluble amyloid precursor protein α -- BDNF brain derived neurotrophic factor -- NAM negative allosteric modulator -- PAM positive allosteric modulator -- LY379268 (1R, 4R, 5S, 6R)-4-Amino-2-oxabicyclo [3.1.0] hexane-4, 6-dicarboxylic acid -- LY2389575 (3S)-N-(2, 4-Dichlorobenzyl)-1-(5-bromopyrimidin-2-yl) pyrrolidinyl-3-amine -- GCM glial conditioned medium -- AG1 arginase 1 -- SR scavenger receptor; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.05.008
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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. Graphical abstract: Highlights: sAPPα and BDNF derived from LY379268-treated astrocytes prevent Aβ neurotoxicity. mGlu3R-induced astroglial Aβ uptake occurs with reduced death of co-cultured neurons. mGlu3R activation reduces Aβ neurotoxicity in pure hippocampal neurons. mGlu2R activation promotes microglial Aβ uptake by a mechanism involving CD11b.