β-amyloid and ATP-induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type-5 receptors.
β-Amyloid (Aβ) oligomers initiate synaptotoxicity following their interaction with the plasma membrane. Several proteins including metabotropic glutamate type 5 receptors (mGluR5s) contribute to this process. We observed an overexpression of mGluR5s in reactive astrocytes surrounding Aβ plaques in brain sections from an Alzheimer's disease mouse model. In a simplified cell culture system, using immunocytochemistry and single molecule imaging, we demonstrated a rapid binding of Aβ oligomers on the plasma membrane of astrocytes. The resulting aggregates of Aβ oligomers led to the diffusional trapping and clustering of mGluR5s. Further, Aβ oligomers induced an increase in ATP release following activation of astroglial mGluR5s by its agonist. ATP slowed mGluR5s diffusion in astrocytes as well as in neurons co-cultured with astrocytes. This effect, which is purinergic receptor-dependent, was not observed in pure neuronal cultures. Thus, Aβ oligomer- and mGluR5-dependent ATP release by astrocytes may contribute to the overall deleterious effect of mGluR5s in Alzheimer's disease. GLIA 2013;61:1673-1686.
Biologie Cellulaire de la Synapse, Institut de Biologie de l'École Normale Supérieure, INSERM U1024-CNRS 8197, Paris 75005, France.
Amulya Nidhi
AN
Shrivastava
Jacob M
JM
Kowalewski
Marianne
M
Renner
Luc
L
Bousset
Annette
A
Koulakoff
Ronald
R
Melki
Christian
C
Giaume
Antoine
A
Triller
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001081:Apyrase / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects*; D053764:Presenilin-1 / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013997:Time Factors
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; C508853:PSEN1 protein, human; D053764:Presenilin-1; D064529:Receptor, Metabotropic Glutamate 5; D000255:Adenosine Triphosphate; D001081:Apyrase; D002118:Calcium
ATP; Alzheimer's disease; mGluR5s; neuroglia signaling; single particle tracking; β-amyloid (Aβ) oligomers