Effects of huanglian-jie-du-tang and its modified formula on the modulation of amyloid-β precursor protein processing in alzheimer's disease models

Siva Sundara Kumar Durairajan, Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University
Ying-Yu Huang, Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University
Pui-Yee Yuen, Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University
Lei-Lei Chen, Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University
Ka-Yan Kwok, Natural Products Chemistry and Analysis Laboratory, School of Chinese Medicine, Hong Kong Baptist University
Liang-Feng Liu, Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University
Ju-Xian Song, Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University
Quan-Bin Han, Natural Products Chemistry and Analysis Laboratory, School of Chinese Medicine, Hong Kong Baptist University
Lei Xue, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University
Sookja K. Chung, Department of Anatomy, Li Ka Shing Faculty of Medicine, University of Hong Kong
Jian-Dong Huang, Department of Biochemistry, Li Ka Shing Faculty of Medicine, University of Hong Kong
Larry Baum, School of Pharmacy, Chinese University of Hong Kong
Sanjib Senapati, Department of Biotechnology, Indian Institute of Technology Madras
Min Li, Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University

Abstract

Huanglian-Jie-Du-Tang (HLJDT) is a famous traditional Chinese herbal formula that has been widely used clinically to treat cerebral ischemia. Recently, we found that berberine, a major alkaloid compound in HLJDT, reduced amyloid-β (Aβ) accumulation in an Alzheimer's disease (AD) mouse model. In this study, we compared the effects of HLJDT, four single component herbs of HLJDT (Rhizoma coptidis (RC), Radix scutellariae (RS), Cortex phellodendri (CP) and Fructus gardenia (FG)) and the modified formula of HLJDT (HLJDT-M, which is free of RS) on the regulatory processing of amyloid-β precursor protein (APP) in an in vitro model of AD. Here we show that treatment with HLJDT-M and its components RC, CP, and the main compound berberine on N2a mouse neuroblastoma cells stably expressing human APP with the Swedish mutation (N2a-SwedAPP) significantly decreased the levels of full-length APP, phosphorylated APP at threonine 668, C-terminal fragments of APP, soluble APP (sAPP)-α and sAPPβ-Swedish and reduced the generation of Aβ peptide in the cell lysates of N2a-SwedAPP. HLJDT-M showed more significant APP- and Aβ- reducing effects than berberine, RC or CP treatment alone. In contrast, HLJDT, its component RS and the main active compound of RS, baicalein, strongly increased the levels of all the metabolic products of APP in the cell lysates. The extract from FG, however, did not influence APP modulation. Interestingly, regular treatment of TgCRND8 APP transgenic mice with baicalein exacerbated the amyloid plaque burden, APP metabolism and Aβ production. Taken together, these data provide convincing evidence that HLJDT and baicalein treatment can increase the amyloidogenic metabolism of APP which is at least partly responsible for the baicalein-mediated Ab plaque increase in the brains of TgCRND8 mice. On the other hand, HLJDT-M significantly decreased all the APP metabolic products including Aβ. Further study of HLJDT-M for therapeutic use in treating AD is warranted. © 2014 Durairajan et al.