Tripchlorolide Attenuates β-amyloid Generation via Suppressing PPARγ-Regulated BACE1 Activity in N2a/APP695 Cells
Tripchlorolide Attenuates β-amyloid Generation via Suppressing PPARγ-Regulated BACE1 Activity in N2a/APP695 Cells
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TripChloride 通过抑制 N2a/APP695 细胞中 PPARγ 调节的 BACE1 活性来减弱 β-淀粉样蛋白的生成
DOI：
10.1007/s12035-015-9542-2
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发表时间：
2016-11-01
影响因子：
5.1
通讯作者：
Chen, Xiao-chun
中科院分区：
文献类型：
--
作者：
Lin, Nan;Chen, Li-min;Chen, Xiao-chun
由于其明显的限速功能，BACE 1（β-分泌酶）似乎是预防阿尔茨海默病（AD）大脑中淀粉样蛋白β（A β）生成的主要靶点。BACE 1的活性受过氧化物酶体增殖物激活受体-γ（过氧化物酶体增殖物激活受体-γ）的调节，过氧化物酶体增殖物激活受体-γ是BACE 1启动子的转录因子结合位点，表明过氧化物酶体增殖物激活受体-γ可能是AD治疗的潜在靶点。几项研究表明，过氧化物酶体增殖物激活受体γ参与非甾体抗炎药（NSAID）对淀粉样β前体蛋白加工的免疫刺激。目前的研究发现，与NSAID化学结构相似的雷公藤（T-4）可降低N2 a-APP 695细胞分泌的A β水平。T-4处理降低了BACE 1的mRNA和蛋白水平以及sAPP β的蛋白水平，sAPP β是BACE 1切割的APP N端片段。该处理还将PPAR γ从细胞质易位至细胞核。有趣的是，T-4与吡格列酮（一种PPAR γ激动剂）一样，抑制N2 a-APP 695细胞中的BACE 1活性，而GW 9662（一种PPAR γ拮抗剂）可减弱这种抑制作用。这些结果表明，T-4可能是一种PPAR γ激动剂，可增强核PPAR γ与BACE 1启动子的结合，进而抑制BACE 1的转录和翻译，抑制BACE 1的活性，并最终减弱A β的产生。由于其改变A β生成和保护中枢神经系统免受A β神经毒性的能力，T-4可作为调节阿尔茨海默病中A β相关病理的有前途的药物。
Due to its apparent rate-limiting function, BACE1 (beta-secretase) appears to be a prime target for prevention of amyloid-beta (A beta) generation in brains with Alzheimer's disease (AD). The activity of BACE1 is regulated by peroxisome proliferator-activated receptor-gamma (PPAR gamma), a transcription factor binding site of the BACE1 promoter, indicating that PPAR gamma may be a potential target for AD treatment. Several studies have demonstrated that PPAR gamma activation is involved in the immunostimulation of amyloid-beta precursor protein processing by nonsteroidal anti-inflammatory drugs (NSAIDs). The present study found that tripchlorolide (T-4), with a similar chemical structure to that of NSAIDs, decreased the levels of A beta secreted in N2a-APP695 cells. T-4 treatment reduced the mRNA and protein levels of BACE1 and the protein level of sAPP beta, a cleaved N-terminal fragment of APP by BACE1. The treatment also translocated PPAR gamma from cytoplasm to nuclear. Intriguingly, T-4, like pioglitazone (a PPAR gamma agonist), suppressed the BACE1 activity in N2a-APP695 cells, which was attenuated by GW9662 (a PPAR gamma antagonist). These results indicate that T-4 may be a PPAR gamma agonist to enhance the binding of nuclear PPAR gamma to the BACE1 promoter, which may in turn inhibit the transcription and translation of BACE1, suppress the activity of BACE1, and ultimately attenuate the generation of A beta. Due to its capability to alter A beta generation and to protect central neural system against the neurotoxicity of A beta, T-4 may serve as a promising agent in modulating A beta-related pathology in Alzheimer's disease.