FLZ alleviates the memory deficits in transgenic mouse model of Alzheimer's disease via decreasing beta-amyloid production and tau hyperphosphorylation.
FLZ alleviates the memory deficits in transgenic mouse model of Alzheimer's disease via decreasing beta-amyloid production and tau hyperphosphorylation.
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DOI：
10.1371/journal.pone.0078033
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhang D
中科院分区：
文献类型：
--
作者：
Bao XQ;Li N;Wang T;Kong XC;Tai WJ;Sun H;Zhang D
阿尔茨海默病(AD)是世界范围内最常见的痴呆病因，其主要特征是聚集的β-淀粉样蛋白(A-β)和过度磷酸化的tau。Flz是一种新型的天然鳞糖胺的合成衍生物，已被证明可以改善痴呆动物模型的记忆障碍。本研究旨在探讨FLZ对APP/PS1双转基因小鼠和SH-SY5Y(APPwt/Swe)细胞的神经保护作用机制。结果表明，FLZ可明显改善APP/PS1转基因小鼠的记忆障碍，减少SH-SY5Y(APPwt/Swe)细胞的凋亡率。在体内和体外，氟尿嘧啶均显著抑制Aβ的蓄积和tau的磷酸化。机制研究表明，Flz干扰了APP的加工，即降低了β-淀粉样前体蛋白(APP)的磷酸化、APP-羧基末端片段的产生和β-淀粉样前体蛋白裂解酶1(BACE1)的表达。这些结果表明，氟尿嘧啶通过抑制淀粉样蛋白合成途径减少A-β的产生。Flz抑制tau磷酸化的机制研究揭示了Akt/糖原合成酶β(GSK3β)通路的参与。在体内和体外，氟尿嘧啶均能提高AKT活性，抑制GSK3β活性。Flz通过抑制Akt活性抑制β活性和tau磷酸化，提示Akt/Gsk3β通路可能是其抑制tau过度磷酸化的机制之一。这些结果表明，氟尿嘧啶可能是一种潜在的抗AD药物，因为它不仅通过抑制淀粉样蛋白合成APP途径减少了Aβ的产生，而且还减弱了由Akt/Gsk3β介导的tau过度磷酸化。
Alzheimer’s disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated β-amyloid (Aβ) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ’s neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aβ accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased β-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and β-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aβ production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ’s inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3β (GSK3β) pathway. FLZ treatment increased Akt activity and inhibited GSK3β activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3β activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3β pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aβ production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3β.
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DOI：
10.1083/jcb.200301115
发表时间：
2003-10-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee MS;Kao SC;Lemere CA;Xia W;Tseng HC;Zhou Y;Neve R;Ahlijanian MK;Tsai LH
通讯作者：
Tsai LH
影响因子：
--
作者：
Lemere, Cynthia A.
通讯作者：
Lemere, Cynthia A.
DOI：
10.1111/j.1742-7843.2007.00138.x
发表时间：
2007-12-01
影响因子：
3.1
作者：
Fang, Fang;Liu, Gengtao
通讯作者：
Liu, Gengtao
影响因子：
4
作者：
Hou, Yan;Yu, Young-Beob;Luo, Yuan
通讯作者：
Luo, Yuan
影响因子：
82.9
作者：
Shankar, Ganesh M.;Li, Shaomin;Selkoe, Dennis J.
通讯作者：
Selkoe, Dennis J.