期刊
NEUROPHARMACOLOGY
卷 123, 期 -, 页码 274-286出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2017.05.008
关键词
Metabotropic glutamate receptors; Alzheimer's disease; Neuron-glia interaction; Amyloid beta clearance; sAPP alpha; BDNF
资金
- National Research Council (CONICET) [RD 20140113-0119]
- ANPCyT [PICT0642, PICT0752]
- CONICET [PIP630]
- UBA [20020130100120BA]
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 sAPP alpha. 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 (A(beta). Conditioned medium from LY379268-treated astrocytes protected hippocampal neurons from A beta-induced cell death. Immunodepletion of sAPP alpha 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 A beta neurotoxicity. LY379268 was also able to decrease A beta-induced neuron death by acting directly on neuronal mGlu3R. On the other hand, LY379268 increased A beta uptake in astrocytes and microglia. Indeed, and more importantly, a reduction in A beta-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 A beta neurotoxicity: (i) it increases the release of protective neurotrophins such as sAPP alpha and BDNF, and (ii) it induces amyloid removal from extracellular space by glia-mediated phagocytosis. (C) 2017 Elsevier Ltd. All rights reserved.
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