以多羥基薑黃素衍生物提升腦啡肽酶來預防阿茲海默症

Abstract

腦啡肽酶(neprilysin)被視為最重要的類澱粉降解蛋白，由於它在生理上的表現量不僅隨著年齡的增長而遞減和類澱粉的堆積情況也呈現負相關，故被認為對於偶發性阿茲海默症的促成有著密切的關聯。近幾年的許多研究中都表示調控腦啡肽酶增加其表現量對於阿茲海默症的預防與治療是有希望的。本篇實驗中，我們利用先前已建立用來偵測類澱粉貝塔蛋白降解的高靈敏螢光分析平台來篩選25種薑黃素衍生物對於調控腦啡肽酶活性的能力。我們意外地發現了雙羥基薑黃素、單羥基去甲基薑黃素、單羥基去雙甲基薑黃素及雙羥基去雙甲基薑黃素這4種化合物會增加腦啡肽酶的活性而薑黃素本身卻不會。而此我們在一系列細胞以及動物實驗的數據結果中，證實了這些多羥基薑黃素衍生物調控，使腦啡肽酶活性的增加，乃是由其信使核糖核酸和蛋白質的表現量調控增加所造成。最後我們在動物中，發現餵食雙基因轉殖鼠(APPswe/PS1dE9)單羥基去甲基薑黃素能增加腦內腦啡肽酶的量，並減少大腦皮層及海馬迴內類澱粉貝塔蛋白的堆積。透過此篇實驗的結果，相信此類多羥基薑黃素衍生物在防止罹患阿茲海默症上具有預防的潛力。

Neprilysin (NEP) is the most important Aβ-degrading enzyme. Its expression level decreases with age and inversely correlated with amyloid accumulation, suggesting its correlation with the late-onset of Alzheimer’s disease. Recently, many reports showed that upregulating NEP level is a promising strategy in the prevention and therapy of Alzheimer’s disease. Here, we used a sensitive fluorescence-based Aβ digestion assay to screen 25 curcumin analogs for their ability to upregulate NEP activity. We surprisingly found that four compounds, dihydroxylated curcumin, monohydroxylated demethoxycurcumin, and mono- and di-hydroxylated bisdemethoxycurcumin, increased NEP activity, while curcumin did not. The ability of these polyhydroxycurcuminoids on upregulating NEP was further confirmed by mRNA and protein expression levels in the cell and mouse models. Finally, feeding of monohydroxylated demethoxycurcumin to APPswe/PS1dE9 double transgenic mice upregulated NEP levels in the brain and reduced Aβ accumulation in the hippocampus and cortex. These polyhydroxycurcuminoids offer hope in the prevention of Alzheimer’s disease.