Akt-activated GSK3β inhibitory peptide effectively blocks tau hyperphosphorylation.

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Archives of Pharmacal Research Pub Date : 2024-09-26 DOI:10.1007/s12272-024-01513-1
Eunjin Lee, Yujeong Lee, Seonguk Yang, Eun Ji Gong, Jaehoon Kim, Nam-Chul Ha, Dong-Gyu Jo, Mark P Mattson, Jaewon Lee
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Abstract

Tau hyperphosphorylation and accumulation in neurofibrillary tangles are closely associated with cognitive deficits in Alzheimer's disease (AD). Glycogen synthase kinase 3β (GSK3β) overexpression has been implicated in tau hyperphosphorylation, and many GSK3β inhibitors have been developed as potential therapeutic candidates for AD. However, the potent GSK3β inhibitors produced are prone to side effects because they can interfere with the basic functions of GSK3β. We previously found that when the phosphorylated PPPSPxS motifs in Wnt coreceptor LRP6 can directly inhibit GSK3β, and thus, we produced a novel GSK3β inhibitory peptide (GIP), specifically activated by Akt, by combining the PPPSPxS motif of LRP6 and the Akt targeted sequence (RxRxxS) of GSK3β. GIP effectively blocked GSK3β-induced tau phosphorylation in hippocampal homogenates and, when fused with a cell-permeable sequence, attenuated Aβ-induced tau phosphorylation in human neuroblastoma cells and inhibited cell death. An in vivo study using a 3 × Tg-AD mouse model revealed that intravenous GIP significantly reduced tau phosphorylation in the hippocampus without affecting Aβ plaque levels or neuroinflammation and ameliorated memory defects. The study provides a novel neuroprotective drug development strategy targeting tau hyperphosphorylation in AD.

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Akt 激活的 GSK3β 抑制肽能有效阻止 tau 过度磷酸化。
神经纤维缠结中的 Tau 过度磷酸化和积累与阿尔茨海默病(AD)的认知障碍密切相关。糖原合酶激酶 3β(GSK3β)的过度表达与 Tau 过度磷酸化有关,许多 GSK3β 抑制剂已被开发为治疗 AD 的潜在候选药物。然而,所生产的强效GSK3β抑制剂容易产生副作用,因为它们会干扰GSK3β的基本功能。因此,我们将 LRP6 的 PPPSPxS 基序与 GSK3β 的 Akt 靶向序列(RxRxxS)相结合,制备出了一种新型的 GSK3β 抑制肽(GIP),它能被 Akt 特异性激活。GIP 能有效阻断 GSK3β 在海马匀浆中诱导的 tau 磷酸化,当与细胞渗透性序列融合时,能减轻 Aβ 在人神经母细胞瘤细胞中诱导的 tau 磷酸化,并抑制细胞死亡。一项使用 3 × Tg-AD 小鼠模型进行的体内研究显示,静脉注射 GIP 能显著降低海马中的 tau 磷酸化,而不影响 Aβ 斑块水平或神经炎症,并能改善记忆缺陷。该研究提供了一种新的神经保护药物开发策略,靶向治疗 AD 中的 tau 过度磷酸化。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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