[beta]-amyloid and ATP-induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type-5 receptors

[beta]-Amyloid (A[beta]) 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 A[beta] 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 A[beta] oligomers on the plasma membrane of astrocytes. The resulting aggregates of A[beta] oligomers led to the diffusional trapping and clustering of mGluR5s. Further, A[beta] 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, A[beta] 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 [PUBLICATION ABSTRACT]