先前研究顯示，海馬迴和大腦皮層中累積的pS14-WWOX可能導致阿茲海默症或其他神經性疾病。調節細胞凋亡的鋅手指樣蛋白(Zfra)可抑制pS14-WWOX積累並恢復三聯轉基因小鼠(3xTg)中阿茲海默症所造成的記憶喪失。在急性期腦創傷(TBI)中，過度表達的WWOX的Tyr33處被磷酸化，並在細胞核中累積造成受影響的區域的神經元死亡。透過免疫組織化學染色法發現， TBI會導致β澱粉樣蛋白聚集、α-突觸核蛋白上調和形成NFT。而Zfra可以顯著地防止β澱粉樣蛋白聚集和NFT形成。此外，我們發現TBI後一年，BALB/c小鼠的大腦中出現了pS14-WWOX和澱粉樣β聚集體的上調。但是受到死亡誘導的小鼠不會誘導pS14-WWOX表達而是會上調pY33-WWOX表達。此外，我們發現在急性與慢性腦創傷中，錨蛋白重複結構40表現量會上升，且會去磷酸化。然而，Zfra4-10胜肽會誘導磷酸化之錨蛋白重複結構40在急性腦創傷時表現，且會降低慢性腦創傷中錨蛋白重複結構40的表現亮。綜合以上觀察，結果表明在小鼠腦中，TBI可能轉變成類AD症狀，而Zfra4-10胜肽可透過調節pY33-WWOX和pS14-WWOX表達以阻止此轉變。

Recently, WWOX is defined as a risk factor for Alzheimer’s disease (AD). Previously, we determined that the accumulation of pS14-WWOX in the brain hippocampus and cortex correlates with the occurrence of AD and probably other neurodegeneration. In addition, we observed that pY33-WWOX is downregulated in AD patients. Zinc finger-like protein that regulates apoptosis (Zfra) suppresses pS14-WWOX accumulation and restores memory loss in triple transgenic mice (3xTg) for AD. The former study showed that when WWOX over-phosphorylation at Tyr33 is accumulated in the nuclei during the acute phase TBI, neuronal death occurs in the impacted area. In this study, we determined that TBI causes Aβ aggregation, alpha-synuclein, and NFT formation during chronic phase TBI. Zfra significantly prevents amyloid-beta aggregates during chronic phase TBI and reduces alpha-synuclein expression during acute phase TBI. Moreover, we discovered that the upregulation of pS14-WWOX occurs, and pY33-WWOX decreases in BALB/c mice brain post TBI for one year. However, mice received trauma do not induce pS14-WWOX expression but upregulate pY33-WWOX expression during acute phase TBI. On the other hand, ankyrin repeat domain 40 (ANR40) was upregulated and was de-phosphorylated at Ser154 during the acute and chronic phase TBI. However, Zfra4-10 peptide upregulated ANR40 phosphorylation at Ser154 during the acute phase TBI and decreased ANR40 expression during the chronic phase TBI. Together, our observations suggest the transition of TBI to AD-like symptom in mice are likely to occur, and that Zfra4-10 peptide prevents the transition by regulating the expression of pY33-WWOX and pS14-WWOX.

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