Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCB256

Poster Communications

MEDI1814, a high-affinity antibody directed to the C-terminus of Aßx-42 is able to rapidly prevent or reverse synaptic plasticity impairment in the rat hippocampus in vivo

T. Ondrejcak1, M. Perkinton2, A. Dudley2, I. Chessell2, A. Billinton2, M. J. Rowan1

1. Pharmacology & Therapeutics and Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland. 2. AstraZeneca Neuroscience iMED, MedImmune, Cambridge, United Kingdom.


Amyloid-β protein (Aβ) plays a pivotal role in the pathogenesis of Alzheimer disease. N-terminus and mid-region directed anti-Aβ antibodies have been shown to have potential therapeutic efficacy based on their ability to reduce Aß oligomer-mediated disruption of synaptic plasticity. It is not clear if antibodies directed to the C-terminus have the same efficacy. Here we examined the ability of a high affinity monoclonal antibody directed to the C-terminus of Aßx-42 to prevent or reverse the inhibition of long-term potentiation (LTP) by synthetic Aß aggregates in the hippocampus of urethane (1.5 g/kg i.p.) -anaesthetized rats (male Lister Hooded, 250-350 g. First, we evaluated the effects of acute intracerebroventricular co-injection of MEDI1814 (0.3 mg per rat) with soluble synthetic Aβ1-42 enriched in protofibrils (480 pmol). Whereas i.c.v. administration of MEDI1814 fully abrogated the acute inhibition of LTP by Aß (123.1 ± 4.1 vs 110 ± 2.1% in Aß+antibody vehicle group, n=6-7, p<0.05, one-way ANOVA followed by Holm-Sidak post-hoc tests), co-injection of a relatively low affinity Aß antibody, (MEDI8490, Kd ~10nM), was inactive (106.9 ± 1.5%, n=6, p>0.05 compared with Aß+vehicle; p<0.01 compared with the Aß+high affinity antibody group). Next, we examined if systemic passive immunization could prevent or reverse the persistent inhibition of LTP measured in vivo 7 days after a single i.c.v. injection of protofibril-enriched Aß1-42. The Aß (585 pmol) was administered under recovery anaesthesia (ketamine, 80 mg/kg and xylazine, 8 mg/kg, both i.p.). Pretreatment with MEDI1814 systemically via cardiac puncture (3 mg/kg, i.c.) on day 1, fifteen minutes prior to Aß injection, prevented the disruption of LTP measured 7 days later under urethane anaesthesia (124.4 ± 5.1 vs 108.9 ± 2.7% in animals treated with antibody vehicle prior to Aß, n=5-6, p<0.05), whereas the same dose of MEDI8490 did not prevent the Aß-mediated LTP impairment (106.5 ± 2.1%, n=5, p>0.05 compared with vehicle+Aß group; p<0.05 compared with animals given MEDI1814 prior to Aß). Similarly, when a single injection of MEDI1814 (1.5 mg/kg, i.c.) was given on day 7, under urethane anaesthesia, it abrogated the delayed persistent impairment of hippocampal LTP caused by Aß (123.5 ± 2.9 vs 107.2 ± 2.5% in Aß+vehicle group, n=7 in both groups, p<0.001). In contrast, post-Aß treatment with MEDI8490 (1.5 mg/kg, i.c.) was ineffective (109 ± 1.4%, n=6, p>0.05 compared with Aß+vehicle; p<0.01 compared with Aß+MEDI1814-injected animals). In conclusion, intracerebral or systemic administration of a high affinity monoclonal antibody directed to the C-terminus of Aßx-42 is able to rapidly prevent or reverse synaptic plasticity impairment in the rat hippocampus caused by Aβ1-42 aggregates.

Where applicable, experiments conform with Society ethical requirements