eprintid: 1554123
rev_number: 33
eprint_status: archive
userid: 608
dir: disk0/01/55/41/23
datestamp: 2017-04-29 22:34:17
lastmod: 2021-11-01 02:38:48
status_changed: 2017-05-04 10:33:07
type: article
metadata_visibility: show
creators_name: Zhang, D
creators_name: Qi, Y
creators_name: Klyubin, I
creators_name: Ondrejcak, T
creators_name: Sarell, CJ
creators_name: Cuello, AC
creators_name: Collinge, J
creators_name: Rowan, MJ
title: Targeting glutamatergic and cellular prion protein mechanisms of amyloid β-mediated persistent synaptic plasticity disruption: longitudinal studies
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: DF9
divisions: FA5
keywords: APP transgenic rat, Alzheimer's disease, Glutamate-oxalate transaminase, Long-term potentiation, Metabotropic glutamate receptor 5
note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
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.
date: 2017-07-15
date_type: published
official_url: https://doi.org/10.1016/j.neuropharm.2017.03.036
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1288729
doi: 10.1016/j.neuropharm.2017.03.036
pii: S0028-3908(17)30128-4
lyricists_name: Collinge, John
lyricists_id: JCOLL20
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Neuropharmacology
volume: 121
pagerange: 231-246
event_location: England
issn: 1873-7064
citation:        Zhang, D;    Qi, Y;    Klyubin, I;    Ondrejcak, T;    Sarell, CJ;    Cuello, AC;    Collinge, J;           Zhang, D;  Qi, Y;  Klyubin, I;  Ondrejcak, T;  Sarell, CJ;  Cuello, AC;  Collinge, J;  Rowan, MJ;   - view fewer <#>    (2017)    Targeting glutamatergic and cellular prion protein mechanisms of amyloid β-mediated persistent synaptic plasticity disruption: longitudinal studies.                   Neuropharmacology , 121    pp. 231-246.    10.1016/j.neuropharm.2017.03.036 <https://doi.org/10.1016/j.neuropharm.2017.03.036>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1554123/1/Zhang_Targeting_glutamatergic_cellular_prion_protein.pdf