title: Astroglial mGlu3 receptors promote alpha-secretase-mediated amyloid precursor protein cleavage.
abstract: Amyloid precursor protein (APP) shedding yields the Alzheimer's disease (AD)-related peptide amyloid β (Aβ) through β- and γ-secretase cleavage. Alternatively, α-secretase cleavage generates a soluble and neuroprotective fragment (sAPPα) while precludes the production of Aβ. Although metabotropic glutamate (mGlu) receptors were associated with induction of sAPPα production in astrocytes, there was no further evidence regarding the specific subtype receptor or the mechanisms involved in this action. In the present study, we used the dual mGlu2/3 receptor agonist LY379268, which in pure astrocyte cultures selectively activates mGlu3 receptor subtype since mGlu2 receptor subtype is not expressed by these cells. We showed that LY379268 incremented sAPPα release from cultured astrocytes by inducing α-secretases expression, whereas it decreased β-secretase levels. LY379268-induced increase of PPAR-γ levels could be involved in the effect of the agonist on sAPPα release. Using the PDAPP-J20 murine model of AD we described a strong reduction in mGlu2/3 receptor expression in the hippocampus of 5- and 14-month-old transgenic mice compared to control littermates. Moreover, mGlu3 receptor expression is also decreased specifically in hippocampal astrocytes of these transgenic animals as a function of age. Therefore, diminished levels of hippocampal mGlu3 receptors might have implications in the development of the disease in these transgenic mice considering the anti-amyloidogenic action of mGlu3 receptors in astrocytes.
authors.affiliation: Instituto de Investigaciones Biomédicas (INBIOMED), School of Medicine, University of Buenos Aires - CONICET, Paraguay 2155, Ciudad Autónoma de Buenos Aires 1121, Argentina.
authors.forename: Daniela
authors.initials: D
authors.lastname: Durand
authors.affiliation: Instituto de Investigaciones Biomédicas (INBIOMED), School of Medicine, University of Buenos Aires - CONICET, Paraguay 2155, Ciudad Autónoma de Buenos Aires 1121, Argentina.
authors.forename: Lila
authors.initials: L
authors.lastname: Carniglia
authors.affiliation: Laboratorio de Neurobiología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes 2160, Ciudad Autónoma de Buenos Aires 1428, Argentina; Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Ciudad Autónoma de Buenos Aires 1428, Argentina.
authors.forename: Juan
authors.initials: J
authors.lastname: Beauquis
authors.affiliation: Instituto de Investigaciones Biomédicas (INBIOMED), School of Medicine, University of Buenos Aires - CONICET, Paraguay 2155, Ciudad Autónoma de Buenos Aires 1121, Argentina.
authors.forename: Carla
authors.initials: C
authors.lastname: Caruso
authors.affiliation: Laboratorio de Neurobiología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes 2160, Ciudad Autónoma de Buenos Aires 1428, Argentina; Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Ciudad Autónoma de Buenos Aires 1428, Argentina.
authors.forename: Flavia
authors.initials: F
authors.lastname: Saravia
authors.affiliation: Instituto de Investigaciones Biomédicas (INBIOMED), School of Medicine, University of Buenos Aires - CONICET, Paraguay 2155, Ciudad Autónoma de Buenos Aires 1121, Argentina. Electronic address: mlasaga@fmed.uba.ar.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Lasaga
mesh_terms: D000375:Aging; D000596:Amino Acids / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D000596:Amino Acids; D016564:Amyloid beta-Protein Precursor; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D053829:Amyloid Precursor Protein Secretases
keywords: Amyloid precursor protein; Astrocytes; Hippocampus; Metabotropic glutamate receptor 3; PDAPP-J20 mice; Secretases