β-amyloid and ATP-induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type-5 receptors

Abstract

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.

Morphological plasticity of astroglia: Understanding synaptic microenvironment

“…Although such evidence has been essential in advancing our understanding of astroglia‐neuron communication, it leaves unresolved some critical questions regarding molecular physiology of the synaptic microenvironment, and in particular, local astroglial protrusions, on the nanoscale. Single‐molecule tracking of mGluRs and glutamate transporters in cultured astroglia has provided first glimpses on what could be the dynamic molecular micro‐organization of astrocytes (Arizono et al, 2012; Murphy‐Royal et al, 2015; Shrivastava et al, 2013), and STED imaging in organised brain tissue (Tonnesen et al, 2014) has opened up the nanoscopic world of live astroglial architecture in situ . Clearly, further implementation of super‐resolution techniques in organised brain tissue should help to bridge the knowledge gap in our understanding of the molecular micro‐physiology of astroglia and its role in information processing of brain networks.…”

“…However, application of such methods to astroglia is only beginning to emerge. Single‐molecule tracking of mGluRs in cultured astroglia has provided some previously unattainable insights into the molecular dynamic organization of astrocytic compartments (Arizono et al, 2014, 2012; Shrivastava et al, 2013). Most recently, a similar method has unveiled strong, activity‐dependent mobility of glutamate transporters GLT‐1 on the surface of cultured astroglia (Murphy‐Royal et al, 2015), thus opening a new horizon in our understanding of astroglial microphysiology.…”

Astroglial calcium signalling in Alzheimer's disease

“…Already after 1 hour of incubation of cultured astrocytes with 100 nM of β-amyloid, it induced clustering and diffusional trapping of metabotropic glutamate receptor 5 (mGluR5); this in turn activated the receptor and induced release of ATP [124]. At longer exposure times (24-72 h), β-amyloid upregulated the expression of astroglial mGluR5 [125].…”

Astrocyte-mediated metaplasticity in the hippocampus: Help or hindrance?

“…Thus, the participation of mGlu5 in tripartite synaptic signalling has been suggested to be restricted to periods of maturation (Grosche and Reichenbach, 2013). However, in rodent and human brain the expression of astrocytic mGlu5 is increased in several pathological states, even during adulthood (Aronica et al, 2000, Aronica et al, 2001, Ferraguti et al, 2001, Newcombe et al, 2008, Casley et al, 2009, Shrivastava et al, 2013. Indeed, results from these studies suggest that expression of mGlu5 may be a general hallmark of reactive astrocytosis.…”