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.
Highlights
Extracellular senile plaques and phosphorylated tau-associated intraneuronal neurofibrillary tangles (NFTs) are the two classical microscopic pathologies of Alzheimer’s disease (AD) [1]
In contrast with Qiu et al [16], we found that HLJDT increased full length (Fl)-amyloid precursor protein (APP), sAPPa, sAPPb and intracellular Ab in N2a mouse neuroblastoma cells expressing APP with the Swedish mutation (N2a-SwedAPP cells)
We ascertained each extract and compound of HLJDT components for cytotoxicity for at least 48 h at five different concentrations; we considered the non-toxic concentration as the highest concentration that showed more than 90% cell viability (Figure 2)
Summary
Extracellular senile plaques and phosphorylated tau-associated intraneuronal neurofibrillary tangles (NFTs) are the two classical microscopic pathologies of Alzheimer’s disease (AD) [1]. APP is an integral membrane protein processed by the proteases a-secretase or b-secretase to produce a-C terminal fragment (CTF-a) or b-C terminal fragment (CTF-b), respectively. These fragments are subsequently cleaved by c-secretase to produce P3 or Ab respectively, and a cytoplasmic tail dubbed APP-intracellular domain (AICD) [1]. Monomeric Ab (4.3 kDa molecular weight) self-assembles into oligomers. These oligomers eventually deposit as large fibrils in extracellular space, which assemble as amyloid plaques [1,3]. The precise mechanisms by which Ab may induce neurotoxicity are still unknown, several are proposed, including calcium influx, generation of reactive oxygen species (ROS), nitric oxide (NO) production and increased phosphorylation of tau [4]
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