Preparation and Multitarget Anti-AD Activity Study of Chondroitin Sulfate Lithium in AD Mice Induced by Combination of D-Gal/AlCl(3)

Previous studies have demonstrated that both CS and LiCl possess anti-Alzheimer's disease (AD) activities. We prepared chondroitin sulfate-Li (CS-Li) and investigated its effect on AD and explored the possible mechanisms both in vitro and in vivo. We found that CS-Li could inhibit amyloid β (Aβ) aggregation and protect SH-SY5Y cells from Aβ(1-42)-induced cytotoxicity in vitro. In D-gal and AlCl(3)-induced AD mouse model, CS-Li improves the spatial learning and memory abilities of AD mice, reverses the nuclear pyknosis and cell edema, and increases the survival rate of neurons in hippocampus of mice. Moreover, CS-Li significantly increased the levels of GSH-Px, Na(+)/K(+)-ATPase, and ChAT and decreased the levels of MDA and AchE in AD mice. Western blot results demonstrated that CS-Li could decrease the hyperphosphorylation of tau (Ser396/Ser404) by regulating the expression of p-GSK-3β (Ser9) and PP2A and inhibit the expression of proinflammatory factors through inhibiting NF-κB nuclear translocation by activating the MAPK signaling pathways. In a word, CS-Li can delay AD development through multitarget processes, including Aβ aggregation inhibition, oxidative stress damage, tau hyperphosphorylation, and inflammatory response, thereby improves learning and memory abilities.