The Effects of Anti-fibril and Anti-oligomer Antibodies on the Inhibition of LTP by Aß in the Rat Hippocampus In Vivo

Andrew Barry1, Alfred Welzel2, Charles Glabe3, Brian O’Nuallain2, Dominic Walsh2, Michael Rowan1. 1Trinity College, Dublin, Ireland, 2University College, Dublin, Ireland, 3University California, Irvine, United States.

Recent research on Alzheimer’s disease (AD) has focused on the role of soluble oligomers of amyloid-ß protein (Aβ), a proteolytic derivative of the large transmembrane protein amyloid precursor protein (APP). Here we assessed the ability of conformation-selective antibodies to prevent the disruptive effect of different Aß preparations on hippocampal synaptic plasticity in vivo.

Adult male Wistar rats were anaesthetized with urethane (1.5 g/kg, i.p.) and a cannula was implanted in the lateral cerebral ventricle. Electrodes were located in the dorsal hippocampus and field excitatory postsynaptic potentials (EPSPs) were recorded in the stratum radiatum. High frequency stimulation (HFS) at 200 Hz was used to induce long-term potentiation (LTP) 15 min after intracerebroventricular injection (5 μL) of agents. Natural Aβ oligomers and monomers were fractionated using size exclusion chromatography from the conditioned medium of APP-overexpressing CHO cells (7PA2 cells). Soluble synthetic Aß1-42 was prepared by ultracentrifugation.

None of the Aß preparations significantly affected baseline excitatory synaptic transmission. Whereas cell-derived Aß monomers had no significant effect on the induction of LTP, Aβ oligomers strongly inhibited LTP measured 3 h post-HFS (97 ± 4% pre-HFS baseline, n = 5; p > 0.05 compared with baseline, paired t-test; p < 0.05 compared with 141±4% in vehicle-injected controls, n=18, unpaired t-test). Similarly, low-dose (80 pmol) soluble synthetic Aβ1-42 completely inhibited LTP (102 ± 2%, n = 5; p > 0.05 compared with baseline; p < 0.05 compared with vehicle-injected controls).

An anti-oligomer antibody (A11) protected against LTP inhibition when co-incubated and co-injected with natural oligomers (127 ± 2%, n = 5; p < 0.05 compared with baseline and natural oligomer-injected rats; p > 0.05 compared with vehicle) or soluble synthetic Aß1-42 (143 ± 5%, n = 4; p < 0.05 compared with baseline and synthetic Aβ-injected rats; p > 0.05 compared with vehicle). In contrast, an anti-fibril antibody (WO1) failed to abrogate the LTP-inhibiting effects of natural Aβ oligomers (105 ± 4%, n = 5; p > 0.05 compared with baseline and natural oligomer-injected rats) but partly abrogated the LTP-inhibiting effects of low-dose soluble synthetic Aβ1-42 (116 ± 5%, n = 5; p < 0.05 compared with either baseline, soluble synthetic Aβ-injected rats or vehicle). When injected alone, neither of the antibodies had a significant effect on LTP induction.

The present data indicate that the oligomer conformation-selective antibody A11 can fully neutralize the active Aß species in both cell-derived and synthetic soluble Aß whereas the anti-fibril antibody WO1 has only weak activity against the synthetic species.

Supported by Irish Research Council for Science, Engineering and Technology and Science Foundation Ireland.