Accumulations of
amyloid-β (Aβ) 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 Aβ-injected and
presenilin 2 mutant mice through the reduction of accumulated Aβ. To investigate mechanisms of the reduced Aβ accumulation, we examined generation, degradation, efflux and aggregation of Aβ in Swedish AβPP AD model (AβPPsw) 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 Aβ1-42 accumulation in the brains of AβPPsw mice. According to the reduction of Aβ1-42 accumulation, 4-O-methylhonkiol modulated oxidative damage sensitive
enzymes. 4-O-methylhonkiol decreased expression and activity of brain beta-site AβPP cleaving
enzyme (BACE1), but increased clearance of Aβ in the brain through an increase of expressions and activities of Aβ degradation
enzymes;
insulin degrading enzyme and
neprilysin. 4-O-methylhonkiol also increased expression of Aβ 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 AβPPsw 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 AβPPsw mousee brain through inactivation of
caspase-3 and BAX. These results suggest that
4-O-methylhonokiol might prevent the development and progression of AD by reducing Aβ accumulation through an increase of clearance and decrease of Aβ generation via
antioxidant mechanisms.