2012年12月4日 訊 /生物谷BIOON/ --近日,，來自英屬哥倫比亞大學(xué)和溫哥華沿岸衛(wèi)生局的研究者通過研究發(fā)現(xiàn)了一種新型分子,，其可以控制負(fù)責(zé)產(chǎn)生斑塊的蛋白質(zhì)，斑塊的產(chǎn)生是阿爾茲海默癥疾?。ˋD）發(fā)病的信號,。相關(guān)研究成果刊登于國際雜志Journal of Clinical Investigation上。
這種新型分子名為GSK3-beta,，其可以激活表達(dá)蛋白質(zhì)BACE1的基因,，當(dāng)?shù)鞍踪|(zhì)BACE1切斷另外一種名為APP的蛋白質(zhì)時,，淀粉樣蛋白就可以形成小纖維，進(jìn)而在大腦中聚集在一起形成版塊,，最終殺死神經(jīng)細(xì)胞,。
文章中，研究者使用動物模型進(jìn)行研究,，發(fā)現(xiàn)小鼠中GSK3-beta分子效應(yīng)的缺失會引發(fā)BACE1的減少以及大腦中淀粉樣蛋白質(zhì)水平的降低,。此前研究中，研究者揭示了GSK3-beta可以激活神經(jīng)元中扭曲纖維的生長,。
然而,，GSK3-beta分子是一種可以控制關(guān)鍵生理學(xué)功能的多功能酶，用于抑制該分子的藥物并無差別,，而且藥物還可以引發(fā)一系列的副作用,，包括癌癥。研究者Song說,，如果我們能夠發(fā)現(xiàn)一種抑制GSK3-beta和BACE1發(fā)生特殊反應(yīng)的方法,，那么我們就可以更好地對待AD疾病以及抑制疾病的發(fā)展。（生物谷Bioon.com）
doi:10.1172/JCI64516
PMC:
PMID:
Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes
Philip T.T. Ly1, Yili Wu1,2, Haiyan Zou1, Ruitao Wang1, Weihui Zhou2, Ayae Kinoshita3, Mingming Zhang1, Yi Yang1, Fang Cai1, James Woodgett4 and Weihong Song1,2
Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer’s disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β- and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating γ-secretase activity, thereby facilitating Aβ production. There are two highly conserved isoforms of GSK3: GSK3α and GSK3β. We now report that specific inhibition of GSK3β, but not GSK3α, reduced BACE1-mediated cleavage of APP and Aβ production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3β was dependent on NF-κB signaling. Inhibition of GSK3 signaling markedly reduced Aβ deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3β and that inhibition of GSK3 signaling can reduce Aβ neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the β-isoform of GSK3 may be a safe and effective approach for treating AD.
