Amelioration of Cognitive Dysfunction in APP/PS1 Double Transgenic Mice by Long-Term Treatment of 4-O-Methylhonokiol

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease without known ways to cure. A key neuropathologic manifestation of the disease is extracellular deposition of beta-amyloid peptide (Aβ). Specific mechanisms underlying the development of the disease have not yet been fully understood. In this study, we investigated effects of 4-O-methylhonokiol on memory dysfunction in APP/PS1 double transgenic mice. 4-O-methylhonokiol (1 mg/kg for 3 month) significantly reduced deficit in learning and memory of the transgenic mice, as determined by the Morris water maze test and step-through passive avoidance test. Our biochemical analysis suggested that 4-O-methylhonokiol ameliorated Aβ accumulation in the cortex and hippocampus via reduction in beta-site APP-cleaving enzyme 1 expression. In addition, 4-O-methylhonokiol attenuated lipid peroxidation and elevated glutathione peroxidase activity in the double transgenic mice brains. Thus, suppressive effects of 4-O-methylhonokiol on Aβ generation and oxidative stress in the brains of transgenic mice may be responsible for the enhancement in cognitive function. These results suggest that the natural compound has potential to intervene memory deficit and progressive neurodegeneration in AD patients.

Keywords: 4-O-methylhonokiol; APP/PS1 double transgenic; Alzheimer’s disease; Antioxidant; Beta-site APP-cleaving enzyme.

Fig. 1.

4-O-methylhonokiol ameliorates memory impairments in APP/PS1 double transgenic mice. Animals were treated with the natural compound for 3 months and the Morris water maze and passive avoidance tests were performed. With the Morris water maze test, 4-O-methylhonokiol appears to enhance cognitive function of the double transgenic mice (A). There is no significant difference between vehicle-treated animals and the compound-treated animals. The memory consolidation is shown to be better in 4-O-methylhonokiol-treated animals as determined by probe test (B). The step-through passive avoidance memory test reveals that the compound improves contextual memory in the transgenic mice (C). Values are presented as mean ± SD from 10 mice. ^*p<0.05 vs. vehicle treatment. MH=4-O-methylhonokiol.

Fig. 2.

4-O-methylhonokiol attenuates Aβ accumulation in the cortex and hippocampus of the double transgenic mice. Immunohistochemical analysis shows that Aβ is markedly deposited in the brains of the transgenic mice and long-term treatment of 4-O-methylhonokiol alleviates accumulation of the pathogenic peptide (A). Quantification of Aβ accumulation shows that 4-O-methylhonokiol significantly attenuates Aβ deposition both in the cortex and hippocampus (B). ^*p<0.05 vs. vehicle MH=4-O-methylhonokiol.

Fig. 3.

4-O-methylhonokiol suppresses BACE1 expression and Aβ generation. Western blot analysis shows that 4-O-methylhonokiol significantly decreases BACE1 expression in the brain. Aβ level is significantly lower in the 4-O-methylhonokiol-treated brains. Values are presented as mean ± SD from 5 independent blots. ^*p<0.05 vs. vehicle, ^**p<0.01 vs. vehicle. MH=4-O-methylhonokiol.

Fig. 4.

4-O-methylhonokiol increases antioxidant capacity and de creases lipid peroxidation. Long-term treatment of 4-O-methylhonokiol raises the activity of glutathione peroxidase in the brains (A). 4-HNE level is significantly lower in the 4-O-methylhonokiol as assessed by immunohistochemistry (B) and western blots (C). Values are presented as mean ± SD from 5 independent experiments. ^*p<0.05 vs. vehicle, MH=4-O-methylhonokiol, GPx=glutathione peroxidase.