Targeting glutamatergic and cellular prion protein mechanisms of amyloid β-mediated persistent synaptic plasticity disruption: Longitudinal studies

Abstract

Alzheimer's disease amyloid-β (Aβ) oligomers are synaptotoxic, inappropriately increasing extracellular glutamate concentration and glutamate receptor activation to thereby rapidly disrupt synaptic plasticity. Thus, acutely promoting brain glutamate homeostasis with a blood-based scavenging system, glutamate-oxaloacetate transaminase (GOT), and blocking metabotropic glutamate 5 (mGlu5) receptor or its co-receptor cellular prion protein (PrP), prevent the acute inhibition of long-term potentiation (LTP) by exogenous Aβ. Here, we evaluated the time course of the effects of such interventions in the persistent disruptive effects of Aβ oligomers, either exogenously injected in wild type rats or endogenously generated in transgenic rats that model Alzheimer's disease amyloidosis. We report that repeated, but not acute, systemic administration of recombinant GOT type 1, with or without the glutamate co-substrate oxaloacetate, reversed the persistent deleterious effect of exogenous Aβ on synaptic plasticity. Moreover, similar repetitive treatment reversibly abrogated the inhibition of LTP monitored longitudinally in freely behaving transgenic rats. Remarkably, brief repeated treatment with an mGlu5 receptor antagonist, basimglurant, or an antibody that prevents Aβ oligomer binding to PrP, ICSM35, also had similar reversible ameliorative effects in the transgenic rat model. Overall, the present findings support the ongoing development of therapeutics for early Alzheimer's disease based on these complementary approaches.

Anti‐PrPC antibody rescues cognition and synapses in transgenic alzheimer mice

“…However, no dose responsiveness, pharmacokinetic or mechanistic information was available . Administration of other anti‐PrP C antibodies into the CNS or as single bolus injections has demonstrated benefit for long term potentiation deficits caused by either Aßo injection or AD‐related transgenes . However, these studies have not defined the utility or pharmacokinetics of human anti‐PrP C antibodies in an administration paradigm that is amenable to translation for clinical dosing.…”

“…Targeting PrP C , either by genetic deletion of Prnp or binding by anti‐PrP C monoclonal antibodies, has shown promise preclinically . However, antibody studies have been limited to acute electrophysiological outcomes, to intracerebral doses or to large acute doses systemically.…”

Cellular Prion Protein Mediates the Disruption of Hippocampal Synaptic Plasticity by Soluble TauIn Vivo

“…Preventing the binding of infectious prions to cell membrane-anchored PrP is currently under investigation as a means to treat transmissible spongiform encephalopathies (Klyubin et al, 2014b). Intriguingly, the binding of A␤ or ␣-synuclein oligomers to cellular prion protein (PrP C ) disrupts synaptic plasticity and impairs learning (Barry et al, 2011;Freir et al, 2011;Hu et al, 2014;Klyubin et al, 2014b;Ferreira et al, 2017;Zhang et al, 2017) and it has been suggested that PrP C may act as a molecular sensor for a broad range of oligomeric protein ligands (Resenberger et al, 2011;Béland and Roucou, 2012). Intriguingly, like A␤ oligomers (Chen et al, 2010;Freir et al, 2011;Fluharty et al, 2013), full-length recombinant tau has been reported to bind to recombinant PrP in vitro (Wang et al, 2008) raising the prospect that at least some of tau's deleterious synaptic effects are mediated via cellular PrP C .…”

Electrophysiological Investigations of Prion Protein Roles in Health and Disease

“…Similarly, NMDAR is also overactivated by infectious and toxic PrPD species binding to membrane PrPC, likely through the same mechanistic pathway as the oligomers of amyloid beta and alpha-synuclein, which subsequently activates the p38 Mitogen Activated Protein Kinase signaling pathway and induces neurotoxicity [23]. The activation of these downstream signaling pathways significantly disrupts both the propagation of action potentials and synaptic functions leading to impairment of LTP and LTD [15,23,45,47,48]. Together, the evidence suggests that, indirectly, PrPC normally acts as an upstream modulator of a wide variety of intracellular signaling pathways that are essential for neuronal activity.…”