Neuroprotective Effect of Ligustilide through Induction of α-Secretase Processing of Both APP and Klotho in a Mouse Model of Alzheimer's Disease.
Neuroprotective Effect of Ligustilide through Induction of α-Secretase Processing of Both APP and Klotho in a Mouse Model of Alzheimer's Disease.
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在阿尔茨海默氏病小鼠模型中藁本内酯通过诱导 APP 和 Klotho 的 α-分泌酶加工而发挥神经保护作用
DOI：
10.3389/fnagi.2017.00353
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发表时间：
2017
影响因子：
4.8
通讯作者：
Du JR
中科院分区：
文献类型：
--
作者：
Kuang X;Zhou HJ;Thorne AH;Chen XN;Li LJ;Du JR
新的证据表明，α-加工单跨膜蛋白，淀粉样前体蛋白（APP）和抗衰老蛋白Klotho，可能参与阿尔茨海默病（AD）的进展。在动物模型中，天然苯酞类化合物阿替利特（LIG）已被证明可预防衰老和淀粉样蛋白-β（Aβ）诱导的脑功能障碍。本研究旨在探讨LIG对AD双转基因（APP/PS1）小鼠和培养的人细胞认知功能障碍、APP和Klotho代谢的影响及其机制。我们的研究结果表明，LIG治疗显著改善记忆障碍和Aβ水平和斑块负荷。具体而言，LIG可能作为α-分泌酶、去整合素和金属蛋白酶10（ADAM 10）的有效增强剂，导致APP和Klotho的α加工上调，随后可溶性APP片段（sAPPα）和可溶性Klotho（sKL）水平升高，并抑制AD小鼠和培养细胞中的IGF-1/Akt/mTOR信号传导。此外，特异性ADAM 10抑制剂（G1254023 X）在体外有效逆转了LIG诱导的APP和Klotho的α加工，而通过小干扰RNA敲低Klotho基因在体外显著减弱了LIG介导的IGF-1/Akt/mTOR信号转导抑制。结合sAPPα和sKL的神经保护作用以及Akt/mTOR通路抑制诱导的自噬，我们的研究结果表明，LIG对AD的神经保护作用与APP和Klotho的α加工诱导以及潜在的Aβ清除相关。LIG是否能诱导Aβ自噬清除及其机制有待进一步研究。
Emerging evidence suggests that alpha-processing single transmembrane proteins, amyloid precursor protein (APP) and anti-aging protein Klotho, are likely to be involved in the progression of Alzheimer’s disease (AD). The natural phthalide Ligustilide (LIG) has been demonstrated to protect against aging- and amyloid-β (Aβ)-induced brain dysfunction in animal models. The present study is to investigate the effects of LIG on cognitive deficits and metabolism of both APP and Klotho and its underlying mechanism in AD double-transgenic (APP/PS1) mice and cultured human cells. Our results show that treatment with LIG significantly ameliorated memory impairment and Aβ levels and plaques burden. Specifically, LIG might act as a potent enhancer of α-secretase, disintegrin, and metalloprotease 10 (ADAM10), leading to upregulation of alpha-processing of both APP and Klotho and subsequent increases in the levels of both soluble APP fragment (sAPPα) and soluble Klotho (sKL) with inhibition of IGF-1/Akt/mTOR signaling in AD mice and cultured cells. Moreover, the specific ADAM10 inhibitor (G1254023X) effectively reversed LIG-induced alpha-processing of both APP and Klotho in vitro, while Klotho gene knockdown by small interfering RNA significantly blunted LIG-mediated inhibition of IGF-1/Akt/mTOR signaling in vitro. Taken together with the reported neuroprotective effects of both sAPPα and sKL as well as autophagy induction by Akt/mTOR pathway inhibition, our findings suggest that neuroprotection of LIG against AD is associated with induction alpha-processing of APP and Klotho and potential Aβ clearance. Whether LIG might induce Aβ autophagic clearance and the underlying mechanisms need to be further studied.
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自噬参与少突胶质前体介导的淀粉样肽清除
影响因子：
15.1
作者：
Li W;Tang Y;Fan Z;Meng Y;Yang G;Luo J;Ke ZJ
通讯作者：
Ke ZJ
影响因子：
3.7
作者：
Hartl D;Klatt S;Roch M;Konthur Z;Klose J;Willnow TE;Rohe M
通讯作者：
Rohe M
DOI：
10.1073/pnas.96.7.3922
发表时间：
1999-03-30
影响因子：
11.1
作者：
Lammich, S;Kojro, E;Fahrenholz, F
通讯作者：
Fahrenholz, F
影响因子：
11.5
作者：
Abramovitz, Lilach;Rubinek, Tamar;Wolf, Ido
通讯作者：
Wolf, Ido
影响因子：
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作者：
Lemere, Cynthia A.
通讯作者：
Lemere, Cynthia A.