P.2.046 - A novel modulator of AMPA receptors against Alzheimer's Disease pathology: the first in vivo evidence

Abstract

Alzheimer’s disease (AD), the most prevalent form of dementia affecting approximately 33 million people worldwide [1], represents a priority public health problem according to World Health Organization. Despite the considerable progress in understanding the neuropathology of the disease, Alzheimer's Disease remains a complex disorder with undefined initiators and no effective treatment that can block APP misprocessing and Tau hyperphosphorylation [2], the two AD neuropathological mechanisms. Mounting evidence suggest a precipitating role for environmental stress [3] and glutamate signaling in AD while glutamate receptor signaling has been suggested as a therapeutic target against AD synaptic pathology [4]. Hereby, we evaluate the effects of a modulator of AMPA receptor(AMPAR) ona combined rat model of stress/Aβ-driven AD. We have used a chronic unpredictable stress protocol, over 4 weeks, followed by osmotic pump implantation, to deliver either Aβ1-40 or saline (control), while chronic administration of AMPAR at 3 and 10mg/kg followed. A battery of behavioral test was then performed, to access locomotion, anxious-like behavior and cognitive performance. Two-way ANOVA analysis revealed no differences between groups regarding total distance travelled in the Open Field arena, as well as no differences regarding the time spent in the center of the arena. However, when performing Elevated Plus Maze task, the stress/Aβ1-40 showed a decrease in the time as well as in the entries in the open arms (p Our findings demonstrated that this compound is able to revert both recognition and spatial memory deficits in this AD animal model suggesting a beneficial effect of hippocampus- and prefrontal-cortex-dependent function. On-going molecular analysis will provide the mechanistic evidence about the impact of AMPAR modulation on synaptic plasticity and its subsequent impact on the behavioral readout. These studies constitute the first in vivo screening of the potential beneficial effect of a novel compound targeting AMPA receptor and their signaling against AD.