4-O-Methylhonokiol Attenuated Memory Impairment Through Modulation of Oxidative Damage of Enzymes Involving Amyloid- Generation and Accumulation in a Mouse Model of Alzheimer's Disease

Accumulations of amyloid- (A) and oxidative damage are critical pathological mechanisms in the development of Alzheimer's disease (AD). We previously found that 4-O-methylhonokiol, a compound extracted from Magnolia officinalis, improved memory dysfunction in A-injected and presenilin 2 mutant mice through the reduction of accumulated A.T o investigate mechanisms of the reduced A accumulation, we examined generation, degradation, efflux and aggregation of A in Swedish APP AD model (APPsw) mice pre-treated with 4-O-methylhonokiol (1.0 mg/kg) for 3 months. 4-O-methylhonokiol treatment recovered memory impairment and prevented neuronal cell death. This memory improving activity was associated with 4-O-methylhonokiol-induced reduction of A1-42 accumulation in the brains of APPsw mice. According to the reduction of A1-42 accumulation, 4-O-methylhonkiol modulated oxidative damage sensitive enzymes. 4-O-methylhonkiol decreased expression and activity of brain beta-site APP cleaving enzyme (BACE1), but increased clearance of A in the brain through an increase of expressions and activities of A degradation enzymes; insulin degrading enzyme and neprilysin. 4-O-methylhonkiol also increased expression of A transport molecule, low density lipoprotein receptor-related protein-1 in the brain and liver. 4-O- methylhonkiol decreased carbonyl protein and lipid peroxidation, but increased glutathione levels in the brains of APPsw mice suggesting that oxidative damage of protein and lipid is critical in the impairment of those enzyme activities. 4-O-methylhonokiol treatment also prevented neuronal cell death in the APPsw mousee brain through inactivation of caspase-3 and BAX. These