Rezai-Zadeh Kavon, Douglas Shytle R, Bai Yun, Tian Jun, Hou Huayan, Mori Takashi, Zeng Jin, Obregon Demian, Town Terrence, Tan Jun
Department of Psychiatry & Behavioral Medicine, Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, University of South Florida, Tampa, FL 33612, USA.
J Cell Mol Med. 2009 Mar;13(3):574-88. doi: 10.1111/j.1582-4934.2008.00344.x. Epub 2008 Apr 9.
Glycogen synthase kinase 3 (GSK-3) dysregulation is implicated in the two Alzheimer's disease (AD) pathological hallmarks: beta-amyloid plaques and neurofibrillary tangles. GSK-3 inhibitors may abrogate AD pathology by inhibiting amyloidogenic gamma-secretase cleavage of amyloid precursor protein (APP). Here, we report that the citrus bioflavonoid luteolin reduces amyloid-beta (Abeta) peptide generation in both human 'Swedish' mutant APP transgene-bearing neuron-like cells and primary neurons. We also find that luteolin induces changes consistent with GSK-3 inhibition that (i) decrease amyloidogenic gamma-secretase APP processing, and (ii) promote presenilin-1 (PS1) carboxyl-terminal fragment (CTF) phosphorylation. Importantly, we find GSK-3alpha activity is essential for both PS1 CTF phosphorylation and PS1-APP interaction. As validation of these findings in vivo, we find that luteolin, when applied to the Tg2576 mouse model of AD, decreases soluble Abeta levels, reduces GSK-3 activity, and disrupts PS1-APP association. In addition, we find that Tg2576 mice treated with diosmin, a glycoside of a flavonoid structurally similar to luteolin, display significantly reduced Abeta pathology. We suggest that GSK-3 inhibition is a viable therapeutic approach for AD by impacting PS1 phosphorylation-dependent regulation of amyloidogenesis.
糖原合酶激酶3(GSK-3)失调与阿尔茨海默病(AD)的两个病理特征相关:β-淀粉样蛋白斑块和神经原纤维缠结。GSK-3抑制剂可能通过抑制淀粉样前体蛋白(APP)的淀粉样生成性γ-分泌酶切割来消除AD病理。在此,我们报告柑橘生物类黄酮木犀草素可减少携带人类“瑞典”突变APP转基因的神经元样细胞和原代神经元中β-淀粉样蛋白(Aβ)肽的产生。我们还发现木犀草素诱导与GSK-3抑制一致的变化,即(i)减少淀粉样生成性γ-分泌酶对APP的加工,以及(ii)促进早老素-1(PS1)羧基末端片段(CTF)的磷酸化。重要的是,我们发现GSK-3α活性对于PS1 CTF磷酸化和PS1-APP相互作用均至关重要。作为这些体内研究结果的验证,我们发现将木犀草素应用于AD的Tg2576小鼠模型时,可降低可溶性Aβ水平,降低GSK-3活性,并破坏PS1-APP结合。此外,我们发现用香叶木苷(一种结构与木犀草素相似的黄酮类糖苷)处理的Tg2576小鼠显示Aβ病理显著减轻。我们认为,通过影响PS1磷酸化依赖性淀粉样蛋白生成调节,抑制GSK-3是一种可行的AD治疗方法。