Abstract
Amyloid-β (Aβ) is considered partially responsible for cognitive dysfunction in Alzheimer's disease (AD). Resveratrol is known as an anti-neurotoxicity potential natural product, however low blood-brain-barrier (BBB) permissibility and low oral-bioavailability (OB) are the main limitations on its clinical potential. In this study, we illustrated that Pterostilbene (PTS), a kind of resveratrol analog which showed higher scores on BBB and OB, could overcome Aβ-induced neurotoxicity in vitro and in vivo. In silico simulation indicated PTS binding with PDE4A may contribute to its anti-apoptosis and anti-neurotoxicity effects. Behavioral tests further confirmed PTS' potential of overcoming memory deficits in APP/PS1 mice (AD model). Interestingly, PTS also rescued the reducing in dendritic spine density in APP/PS1 mice based on Golgi-Cox staining. Besides, as results of reversing Aβ-induced decreases in cyclic-AMP level, PTS increased the pVASP, pCREB, BDNF, and PSD95 expression. Overall, PTS protects neurons against Aβ-induced neurotoxicity and cognitive dysfunction through regulating the PDE4A-CREB-BDNF pathway. Therefore, targeting on PDE4A, PTS would be a qualified natural product for alleviating Aβ-induced neurotoxicity in AD.