阿茲海默症是老年人中最常見的失智症類型，主要的病理包含了乙型類澱粉蛋白(Aβ)堆積形成的病斑與過度磷酸化濤蛋白(Tau)形成的神經元纖維糾結。目前尚無有效治療阿茲海默症和的藥物。先前的研究顯示WWOX的表現量下降會造成類澱粉前驅蛋白降解，並產生乙型類澱粉蛋白堆積導致神經死亡。同時亦發現WWOX會結合濤蛋白及其磷酸化酶GSK3β、ERK和JNK1。Zinc finger-like protein that regulates apoptosis（Zfra） 是31-氨基酸長的鋅指狀WWOX結合蛋白。我們假設Zfra可以藉由減少乙型類澱粉蛋白堆積及濤蛋白的過度磷酸化，進而改善學習記憶能力受損的症狀。本篇研究方法是使用了帶有APPswe、PS1M146V及TauP301L三種轉殖基因的小鼠（全名129-Psen1tm1Mpm Tg (APPswe,tauP301L) 1Lfa/Mmjax，以下簡稱3xTg），分別在3個月及10個月大的時候進行三個禮拜的Zfra蛋白連續注射，之後使用水迷宮實驗和物件辨認測試進行測試評估老鼠的學習與記憶能力。並收集老鼠的腦組織使用切片分析阿茲海默症相關的病理症狀Aβ病斑、Tau蛋白的磷酸化程度等。實驗結果顯示接受過Zfra注射的3xTg小鼠的學習記憶能力有所改善，小鼠腦中SH3GLB2表現量、TPC6AΔ表現量、tau蛋白磷酸化程度以及Aβ堆積造成的斑塊顯著降低。同時10個月大 Wwox +/-小鼠較同年紀Wwox + / +小鼠有較差的學習記憶能力。本研究的結論是Zfra蛋白可以改善3xTg小鼠的學習記憶能力與減少腦中的 Aβ、TPC6AΔ、磷酸化tau和SH3GLB2蛋白的聚集，且Zfra可能是經由影響WWOX的功能進而改善阿茲海默症相關的症狀

Alzheimer’s disease (AD) is the most common form of dementia in elderly. Pathologically, AD is characterized by high densities of amyloid plaques, constructed by amyloid-β (Aβ), and neurofibrillary tangles, consisted of hyperphosphorylated Tau tangled proteins. There are still no treatments for AD. Previous studies from our laboratory have shown that WWOW downregulation leads to to amyloid precursor protein cleavage, Aβ aggregation and neuronal death. Also, WWOX binds Tau protein and Tau protein kinases (e.g. GSK3β、ERK, and JNK1) so as to block their functional activities. Zinc finger-like protein that regulates apoptosis (Zfra) is a 31-amino-acid protein, and also a WWOX-binding protein. We hypothesize that Zfra reduces the Aβ aggregation and hyperphosphorylation of Tau protein, and improve the learning and memory impairment. In this study, we used the triple transgenic mice (3xTg), 129-Psen1tm1Mpm Tg (APPswe, tauP301L)1Lfa/Mmjax, as an animal model. The mice at the ages of 3 and 10 months were subjected to weekly Zfra injection for three weeks. After that, Morris Water Maze and Object Recognition Test were used to determine the learning and memory ability. AD-related pathologies, including Aβ plaque and Tau phosphorylation level, were then evaluated by brain tissue slides. The results showed that learning and memory impairment were improved in Zfra injection 3xTg mice. In addition, the protein levels of SH3GLB2 and TPC6AΔ along with Tau phosphorylation and Aβ aggregation were significantly decreased. Furthermore, the learning and memory ability of Wwox +/- mice was worse than Wwox + / +mice at the age of 10 month. In conclusion, Zfra protein improves the learning and memory ability of 3xTg mice due, in part, to reduction of SH3GLB2, TPC6AΔ Tau phosphorylation and Aβ deposition. Zfra probably improves the AD-related pathology via enhancement of the WWOX function.

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