Glutamate receptors function as scaffolds for the regulation of β-amyloid and cellular prion protein signaling complexes.

Alison Hamilton,Stephen S G Ferguson,Gerald W Zamponi

doi:10.1186/s13041-015-0107-0

Alison Hamilton, Stephen S G Ferguson + Show 1 more

Open Access

https://doi.org/10.1186/s13041-015-0107-0

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Journal: Molecular brain	Publication Date: Mar 24, 2015
Citations: 153	License type: CC BY 4.0

Affiliation: Western University, University of Calgary

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects 36 million people worldwide, but currently has no effective treatment options. One of the original hallmarks of AD are plaques comprised of beta amyloid (Aβ) and neurofibrillary tangles comprised of phosphorylated Tau protein. However, it is soluble oligomeric Aβ which is more closely correlated with cognitive decline and is therefore considered to be the neurotoxic species. Oligomeric Aβ has recently been shown to form complexes with the glycosylphosphatidylinositol (GPI)-anchored membrane protein, cellular prion protein (PrPc), and these complexes are believed to play an important role in the progression of AD pathogenesis. Glutamate, the major excitatory neurotransmitter is responsible for mediating learning and memory under normal physiological conditions. However, the dysregulation of glutamatergic signaling has also been implicated in a number of neurodegenerative diseases including AD. Glutamate acts via both ionotropic glutamate receptors (iGluR) and metabotropic glutamate receptors (mGluR), each of which have been implicated in AD. There is now growing evidence to suggest that mGluR5 may contribute the AD pathogenesis by acting as scaffolds for the PrPc/Aβ oligomer complex, enabling the propagation of neurotoxic signaling in AD. In addition, PrPc and Aβ oligomer signaling via NMDARs may also contribute to AD pathology. The current review overviews our current understanding of the role of PrPc and Aβ oligomers in regulating glutamate receptor signaling, as well as highlights the importance of understanding these signaling complexes to develop more effective therapeutic strategies to treat AD.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects 36 million people worldwide, but currently has no effective treatment options
As the deletion of metabotropic glutamate receptor 5 (mGluR5) expression reduced Beta amyloid (Aβ) oligomer-mediated synapse loss and mGluR5 antagonist (MTEP) treatment results in the amelioration of cognitive deficits normally observed APPswePS1ΔE9 mice at 9 months of age [9]. Consistent with these observations, we have recently shown that the genetic deletion of mGluR5 in APPswePS1ΔE9 mice results in the reversal of the cognitive deficits associated with this mouse model of AD at both 9 and 12 months of age, and that soluble Aβ oligomer levels and Aβ plaques in APPswePS1ΔE9 mice are reduced in the absence of mGluR5 expression at 12 month of age [12]
In mouse models of AD, it is likely that glutamate reuptake mechanisms are perturbed by Aβ42 oligomers, leading to the buildup of synaptic and extra-synaptic glutamate that triggers prolonged activation of both NMDAR- and metabotropic glutamate receptors (mGluR)-mediated calcium entry resulting in cell damage that may contribute to synaptic loss in AD [101]

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects 36 million people worldwide, but currently has no effective treatment options. The present review will overview the contribution of β-amyloid and cellular prion protein (PrPC) in the regulation of mGluR5 and NMDA receptor signaling.

Results

Conclusion