mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo

Abstract

NMDA-type glutamate receptors (NMDARs) are currently regarded as paramount in the potent and selective disruption of synaptic plasticity by Alzheimer’s disease amyloid β-protein (Aβ). Non-NMDAR mechanisms remain relatively unexplored. Here we describe how Aβ facilitates NMDAR-independent long-term depression of synaptic transmission in the hippocampus in vivo. Synthetic Aβ and Aβ in soluble extracts of Alzheimer’s disease brain usurp endogenous acetylcholine muscarinic receptor-dependent long-term depression, to enable long-term depression that required metabotropic glutamate-5 receptors (mGlu5Rs). We also find that mGlu5Rs are essential for Aβ-mediated inhibition of NMDAR-dependent long-term potentiation in vivo. Blocking Aβ binding to cellular prion protein with antibodies prevents the facilitation of long-term depression. Our findings uncover an overarching role for Aβ-PrPC-mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary.

Role of amyloid β protein receptors in mediating synaptic plasticity

“…This finding supports the results of their previous research (40). Previously, in studies by An et al and Hu et al (41,42) Rowan used antibodies to block PrPc to reduce the influence of Aβ on electrophysiological changes associated with memory, which supports Strittmatter's conclusions [from the study by Gimbel et al (39)] at a conference on European neuroscience. Bitel et al (43) reported that PrP c and Aβ appeared as aggregates and co-localized in a diabetic rabbit model, which suggested that Aβ and PrP c may interact.…”

“…A recent study (65) found that Aβ 42 oligomers are robustly bound to LilrB2-expressing heterologous cells, and LilrB2/PirB2 and Aβ have an affinity at the nanomole level. Relative to monomeric Aβ 42 , oligomerized Aβ 42 peptides are bound to PirB-expressing cells approximately six times as much. Kim et al (65) found that in AD mice, Aβ oligomer damages the LTP of the hippocampus, which needs to combine with PirB.…”

“…Currently, α7nAChR is proven to be an Aβ 42 receptor. Aβ 42 activates the extracellular signal-regulated kinase (ERK2) isoform of the ERK mitogen-activated protein kinase (MAPK) cascade via α7nAChRs, activation of this kinase in the hippocampus is required for contextual and spatial memory formation in mammals (93)(94)(95)(96). The cAMP-regulatory element binding protein is the downstream target of ERK/MAPK and is also a necessary component for hippocampus-dependent memory formation in mammals (97).…”

Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models

“…Interaction between A␤o and PrP C is essential for development of an array of AD features, including activation of certain signaling cascades, synaptotoxicity, inhibition of long term potentiation, memory impairment, and decreased survival in mice (25,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). However, it was also observed that A␤o can induce AD-like phenotypes independently of PrP C in J20 mice (44) and in some in vitro studies (23,24,45).…”

Therapeutic Molecules and Endogenous Ligands Regulate the Interaction between Brain Cellular Prion Protein (PrPC) and Metabotropic Glutamate Receptor 5 (mGluR5)

“…Therefore, it is not surprising that multiple A␤o-induced AD-related deficits are dependent on the presence of both PrP C and mGluR5. Some examples include A␤o-triggered reduction of LTP and enhancement of LTD, activation of intracellular Fyn kinase, A␤o-induced dendritic spine loss, and spatial learning and memory deficits in APP/PS1 transgenic mice (19,30,41,42).…”