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Triptolide treatment reduces Alzheimer's disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD.

ABSTRACT: The complex pathogenesis of Alzheimer's disease (AD) involves multiple contributing factors, including amyloid β (Aβ) peptide accumulation, inflammation and oxidative stress. Effective therapeutic strategies for AD are still urgently needed. Triptolide is the major active compound extracted from Tripterygium wilfordii Hook.f., a traditional Chinese medicinal herb that is commonly used to treat inflammatory diseases. The 5-month-old 5XFAD mice, which carry five familial AD mutations in the β-amyloid precursor protein (APP) and presenilin-1 (PS1) genes, were treated with triptolide for 8 weeks. We observed enhanced spatial learning performances, and attenuated Aβ production and deposition in the brain. Triptolide also inhibited the processing of amyloidogenic APP, as well as the expression of βAPP-cleaving enzyme-1 (BACE1) both in vivo and in vitro. In addition, triptolide exerted anti-inflammatory and anti-oxidative effects on the transgenic mouse brain. Triptolide therefore confers protection against the effects of AD in our mouse model and is emerging as a promising therapeutic candidate drug for AD.

SUBMITTER: Wang Q

PROVIDER: S-EPMC4257007 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Triptolide treatment reduces Alzheimer's disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD.

Wang Qi Q Xiao Bing B Cui Shuqin S Song Hailong H Qian Yanjing Y Dong Lin L An Haiting H Cui Yanqiu Y Zhang Wenjing W He Yi Y Zhang Jianliang J Yang Jian J Zhang Feilong F Hu Guanzheng G Gong Xiaoli X Yan Zhen Z Zheng Yan Y Wang Xiaomin X

Disease models & mechanisms 20141201 12

The complex pathogenesis of Alzheimer's disease (AD) involves multiple contributing factors, including amyloid β (Aβ) peptide accumulation, inflammation and oxidative stress. Effective therapeutic strategies for AD are still urgently needed. Triptolide is the major active compound extracted from Tripterygium wilfordii Hook.f., a traditional Chinese medicinal herb that is commonly used to treat inflammatory diseases. The 5-month-old 5XFAD mice, which carry five familial AD mutations in the β-amyl ...[more]

PMID: 25481013

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Project description:Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated in vitro and in vivo. In vitro studies used SH-SY5Y cells under oxidative stress conditions to assess BACE1 expression, while in vivo effects were studied in 3xTg-AD mice following one month of oral RA-PR058 treatment. Behavioral assessments, biochemical analyses, transcriptomic profiling, and pharmacokinetic evaluations were performed to determine the efficacy of RA-PR058. RA-PR058 significantly reduced oxidative stress-induced BACE1 expression in vitro and decreased cortical BACE1 expression in 3xTg-AD mice. In vivo treatment alleviated anxiety-like behavior and reduced tau phosphorylation at disease-relevant sites (Ser202/Thr205, Thr231, and Ser396). Transcriptomic analysis revealed RA-PR058-mediated gene expression changes related to central nervous system development, response to hypoxia, and neuroactive ligand-receptor interactions, suggesting broader regulatory effects on AD-related pathways. Pharmacokinetic analysis demonstrated that RA-PR058 exhibits high metabolic stability, minimal cytochrome P450 interactions, and moderate blood-brain barrier penetration. RA-PR058 demonstrates potential as a multi-target AD therapeutic by reducing BACE1 expression, tau hyperphosphorylation, and anxiety-like behavior, coupled with favorable pharmacokinetics. Additional studies are needed to assess cognitive effects and clarify molecular mechanisms, but RA-PR058 may represent a promising advancement in addressing AD's complex pathology.

Dataset Information

Triptolide treatment reduces Alzheimer's disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD.

Publications

Triptolide treatment reduces Alzheimer's disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD.

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