title: Effects of Huanglian-Jie-Du-Tang and its modified formula on the modulation of amyloid-β precursor protein processing in Alzheimer's disease models.
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 Aβ 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.
authors.affiliation: Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Siva Sundara Kumar
authors.initials: SS
authors.lastname: Durairajan
authors.affiliation: Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Huang
authors.affiliation: Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Pui-Yee
authors.initials: PY
authors.lastname: Yuen
authors.affiliation: Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Chen
authors.affiliation: Natural Products Chemistry & Analysis Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Ka-Yan
authors.initials: KY
authors.lastname: Kwok
authors.affiliation: Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Liang-Feng
authors.initials: LF
authors.lastname: Liu
authors.affiliation: Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Ju-Xian
authors.initials: JX
authors.lastname: Song
authors.affiliation: Natural Products Chemistry & Analysis Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Quan-Bin
authors.initials: QB
authors.lastname: Han
authors.affiliation: Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xue
authors.affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
authors.affiliation: Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Huang
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Larry
authors.initials: L
authors.lastname: Baum
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Senapati
authors.affiliation: Neuroscience Research Laboratory, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001599:Berberine / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D044950:Flavanones / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects
chemical_list: D016564:Amyloid beta-Protein Precursor; D004365:Drugs, Chinese Herbal; D044950:Flavanones; C061676:oren gedoku to; D001599:Berberine; C006680:baicalein