409 Assessing the preclinical potential of the antidepressant agomelatine for Alzheimer’s disease

Abstract

Objectives/Goals: Alzheimer’s disease (AD) has limited treatments and an extremely high rate of clinical trial failure. Through a collaborative effort, Agomelatine (AGO) was identified as having repurposing potential for AD. This study sets out to evaluate the preclinical potential of AGO for the treatment of AD. Methods/Study Population: The TgF344-AD rat model (expresses human mutant “Swedish” amyloid-precursor protein and a Δ exon 9 presenilin 1) was used to test AGO’s potential to reduce cognitive deficits and neuropathology. The model was chosen due to its age-dependent progressive AD pathology and cognitive decline. Treatment with AGO at ~10 mg/kg body weight/day began at 5 months of age (pre-pathology) and continued until 11 months of age when cognitive testing (active place avoidance task) and tissue collection occurred. Immunohistochemistry was used to evaluate amyloid beta plaque burden and microglial response in the hippocampus. Results/Anticipated Results: AGO-treated female TgF344-AD rats showed reduced cognitive deficits with an increased latency to first entrance in aPAT testing compared to nontreated transgenic littermates. There were no differences between the cognitive performance of AGO treated and untreated male TgF344-AD rats. Interestingly, this reduced cognitive deficit did not correlate with decreased amyloid beta pathology in female AGO-treated rats yet male transgenic treated rats did have decreased amyloid burden in the dentate gyrus (DG) of the hippocampus. AGO modulated microglial activation in the DG of female transgenic rats. Discussion/Significance of Impact: AGO reduced cognitive deficits in females, but did not change their amyloid burden. This suggests that AGO could increase resilience to amyloid deposition in female rats. With the recent development of amyloid targeting drugs, novel non-amyloidogenic treatments have a large translational potential.