title: 4-O-methylhonokiol attenuated memory impairment through modulation of oxidative damage of enzymes involving amyloid-β generation and accumulation in a mouse model of Alzheimer's disease.
abstract: 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.
authors.affiliation: College of Pharmacy, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Korea.
authors.forename: Im Seop
authors.initials: IS
authors.lastname: Choi
authors.forename: Young-Jung
authors.initials: YJ
authors.lastname: Lee
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Choi
authors.forename: Yong Kyung
authors.initials: YK
authors.lastname: Lee
authors.forename: Yeun Hee
authors.initials: YH
authors.lastname: Lee
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Kim
authors.forename: Young Heui
authors.initials: YH
authors.lastname: Kim
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Jae Kyung
authors.initials: JK
authors.lastname: Jung
authors.forename: Yeo Pyo
authors.initials: YP
authors.lastname: Yun
authors.forename: Ki-Wan
authors.initials: KW
authors.lastname: Oh
authors.forename: Dae Youn
authors.initials: DY
authors.lastname: Hwang
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002942:Circular Dichroism / Q000379:methods; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D017705:Lignans / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000378:metabolism; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D050050:Protein Carbonylation / Q000187:drug effects / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics
chemical_list: C542058:4-O-methylhonokiol; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001713:Biphenyl Compounds; D017705:Lignans; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases; D015260:Neprilysin