Up-regulation of astrocyte metabotropic glutamate receptor 5 by amyloid-β peptide.
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.
Casley
Christopher S
CS
Eli Lilly & Company Limited, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UK.
Lakics
Viktor
V
Lee
Hyoung-gon
HG
Broad
Lisa M
LM
Day
Theresa A
TA
Cluett
Tricia
T
Smith
Mark A
MA
O'Neill
Michael J
MJ
Kingston
Ann E
AE
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D002118:Calcium; D015220:Calcium Channels; D010446:Peptide Fragments; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D043562:Receptors, G-Protein-Coupled; D018092:Kainic Acid Receptors; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; C078592:amyloid beta-protein (1-40)