Up-regulation of astrocyte metabotropic glutamate receptor 5 by amyloid-β peptide

• Published in: Brain research Vol. 1260; pp. 65 - 75
• Main Authors: Casley, Christopher S, Lakics, Viktor, Lee, Hyoung-gon, Broad, Lisa M, Day, Theresa A, Cluett, Tricia, Smith, Mark A, O'Neill, Michael J, Kingston, Ann E
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 13.03.2009; Elsevier
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Amyloid beta protein; Amyloid beta-Peptides - metabolism; Animals; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Biological and medical sciences; Calcium - metabolism; Calcium Channels - metabolism; Calcium mobilization; Cells, Cultured; Cerebral Cortex - metabolism; Fundamental and applied biological sciences. Psychology; Hippocampus - metabolism; Humans; Intracellular Space - metabolism; Isolated neuron and nerve. Neuroglia; mGlu5; Mice, Inbred C57BL; Middle Aged; Neurology; Peptide Fragments - metabolism; Receptor, Metabotropic Glutamate 5 - metabolism; Receptors, AMPA - metabolism; Receptors, G-Protein-Coupled - metabolism; Receptors, Kainic Acid - metabolism; RNA, Messenger - metabolism; Time Factors; Up-Regulation; Vertebrates: nervous system and sense organs; Calcium mobilization; mGlu5; AD; Amyloid beta protein; Astrocytes; Cerebral cortex; Calcium; Neuroglia; Rodentia; Central nervous system; Glutamate receptor; Astrocyte; Encephalon; Mobilization; Vertebrata; Mammalia; Metabotropic receptor; Mouse; β Amyloid protein; Animal
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2008.12.082

Abstract The effects of amyloid-beta peptide (Aβ) on astrocyte responses to activation of mGlu5 receptors have been investigated using calcium imaging. Pre-incubation with Aβ1–40 peptide for up to 72 h produced a time- and concentration-dependent 2–4 fold enhancement in the magnitude of the intracellular calcium mobilization response to the group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG). In contrast, pre-treatment with Aβ1–40 did not alter the calcium responses induced by other G protein coupled- or ion channel-receptors. Aβ 1–40-enhanced DHPG responses were blocked by the mGlu5 antagonist MPEP but not by inhibitors of voltage dependent calcium channels or by the AMPA/KA receptor antagonist CNQX. Up-regulation of mGlu5 coupled responses was associated with significant increases in astrocyte mGlu5 receptor- mRNA and -protein expression after preincubation with Aβ . The changes observed in vitro were consistent with results obtained from human Alzheimer's disease (AD) patients. Immunostaining for mGlu5 receptors was increased on astrocytes which were colocalized with Aβ plaques in hippocampal tissue from AD patients compared to age-matched controls. These results suggest that modulation of mGlu5 receptors in astrocytes could be an important mechanism in determining the progression of pathology in AD.