Nobiletin restoring β-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and memory deterioration. Production and accumulation of β-amyloid peptide (Aβ) is central to the pathogenesis of AD. Recent studies have demonstrated that PKA/CREB-dependent signaling pathway and long-term potentiation are inhibited by sublethal concentrations of Aβ1–42 in cultured hippocampus neurons. Here, we examined the effects of nobiletin on the Aβ-induced inhibition of CREB phosphorylation in cultured rat hippocampus neurons. A sublethal concentration of Aβ1–42 or Aβ1–40 decreased glutamate-induced CREB phosphorylation, whereas pretreatment with nobiletin reversed the Aβ-induced decrease in CREB phosphorylation. The effects of nobiletin on impairment of learning ability were also examined in chronically Aβ1–40 infused AD model rats using the eight-arm radial maze. In the AD model rats, nobiletin showed protective effects on Aβ1–40-induced impairment of learning ability. These results suggest that nobiletin has the potential for becoming a novel lead compound for drug development for AD.