PPARδ agonist GW0742 ameliorates Aβ1–42-induced hippocampal neurotoxicity in mice

Abstract

Amyloid-β deposition is thought to be associated with memory deficits, neuroinflammation, apoptotic responses, and progressive neuronal death manifested in Alzheimer's disease. Peroxisome proliferator-activated receptor δ (PPARδ) is a transcription factor with potent anti-inflammatory effect. In the current study, the effect of GW0742, a selective PPARδ agonist, on Aβ1-42-induced neurotoxicity was investigated in the hippocampus of mice. Intra-hippocampal infusion of aggregated Aβ1-42 oligomer (410pmol/mouse) remarkably damaged learning and memory in the Morris water maze (MWM) and Y-maze tests, accompanied by decreased expression of PPARδ in the hippocampus as confirmed by Western blot. Intra-hippocampal infusion of GW0742 (1.06mM/mouse) significantly improved Aβ1-42-induced memory deficits in mice, reversed Aβ1-42-induced hippocampal PPARδ down-regulation and repressed Aβ1-42-triggered neuroinflammatory and apoptotic responses, indicated by decreased nuclear NF-κB p65, TNF-α, IL-1β as well as a decrease in cleaved caspase-3 and increased ratio of Bcl-2/Bax in the hippocampus. These results suggest that PPARδ activation ameliorates Aβ1-42-induced hippocampal neurotoxicity, and it might play a crucial role in Alzheimer's disease.