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

Article type: Research Article

Authors: Choi, Im Seop^{a; b} | Lee, Young-Jung^{a; b} | Choi, Dong-Young^{a; c} | Lee, Yong Kyung^a | Lee, Yeun Hee^a | Kim, Ki Ho^d | Kim, Young Heui^d | Jeon, Young Ho^e | Kim, Eun Hee^f | Han, Sang Bae^{a; b; c} | Jung, Jae Kyung^{a; b} | Yun, Yeo Pyo^a | Oh, Ki-Wan^a | Hwang, Dae Youn^g | Hong, Jin Tae^{a; b; c; *}

Affiliations: [a] College of Pharmacy, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Korea | [b] Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Korea | [c] CBITRC, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Korea | [d] R&D Center, Bioland Ltd., Songjeong, Byongchon, Cheonan-Si, Chungnam, Korea | [e] College of Pharmacy, Korea University, Jochiwon, Yeongi, Chungnam, Republic of Korea | [f] Korea Basic Science Institute, Ochang, Cheongwon, Chungbuk, Korea | [g] Department of Biomaterial Science, Pusan National University, Miryang, Kyungnam, Korea

Correspondence: [*] Correspondence to: Jin Tae Hong, Ph.D., College of Pharmacy, Chungbuk National University, 12, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Korea. Tel.: +82 43 261 2813; Fax: +82 43 268 2732; E-mail: [email protected].

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.

Keywords: Alzheimer's disease, amyloid-β, AβPPsw mouse, 4-O-methylhonokiol, oxidative stress

DOI: 10.3233/JAD-2011-110545

Journal: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 127-141, 2011