人類 WWOX 基因最近被認為是阿爾茨海默病 (AD) 的危險因素。WWOX 蛋白功能缺陷或下調可能導致大腦中不正常的蛋白聚集，最終導致 AD 的發生。先前的研究中，證實了 WWOX 的缺乏會引發 TRAPPC6A、TIAF1、tau 和 Aβ 的聚集。臨床的病理特徵發現在中年健康個體（40-70 歲）和老年 AD 患者（70-100 歲）的大腦皮層和海馬迴中發現了 TRAPPC6A、TIAF1聚集和Aβ的形成。研究中，我們發現 HAson8（透明質酸超聲處理 8 小時）和bifitose共同治療顯著減輕了三重轉基因小鼠（3×Tg）AD的病程，如通過新型物體識別測試（ORT）和莫里斯水迷宮確定調控了海馬迴中非空間和空間學習和記憶的表現。在組織學檢查中，HAson8 顯著抑制了12個月大的 3xTg 小鼠海馬迴中 Aβ 和 pT181-Tau 的聚集，以及發炎性小膠質細胞和星形膠質細胞的活化。此外， bifitose 上調了 WWOX，而 HAson8 顯著抑制海馬迴中促進 AD 病程的 pS14-WWOX的表達。值得注意的是，HAson8 顯著上調了海馬迴中神經幹細胞 Sox2 與中間神經元parvalbumin 的增加。 HAson8 激活脾臟 Hyal-2+ Z 淋巴細胞，並且將激活的 Z 細胞轉移到新受體 3xTg 老鼠使這些小鼠能夠在第 9 個月恢復記憶喪失。最後我們發現HAson8/bifitose 抑制了腸道中促進 AD 的厚壁菌門和擬桿菌門的數量，從而減輕了 3xTg-AD小鼠的進展。總之，HAson8 和 bifitose 一起通過抑制發炎性神經膠質細胞、上調 Z 細胞和神經幹細胞以及減少AD 的腸道細菌，有效減輕 3xTg-AD小鼠的進展。

Human WWOX gene is a recently recognized as a risk factor for Alzheimer’s disease (AD). Functional deficiency or downregulation of WWOX protein may lead to slow protein aggregation in the brain that contributes to the pathogenesis of AD. Previously, we demonstrated that WWOX deficiency initiates the aggregation of TRAPPC6A, TIAF1, tau and Aβ. TRAPPC6A aggregates or plaques have been found in the brain cortex and hippocampus in middle-aged healthy individuals (aged 40 to 70) and old AD patients (70-100 years old). Here, we determined that HAson8 (hyaluronan sonicated for 8 hr) and bifitose together significantly mitigated AD progression in triple-transgenic mouse (3×Tg) model for AD, as determined by novel object recognition test (ORT) and Morris water maze for hippocampus-dependent, non-spatial and spatial learning and memory. By immunohistochemistry, HAson8 significantly suppressed the aggregation of Aβ and pT181-Tau and the levels of inflammatory microglia and astrocytes in 12-month-old 3xTg mouse hippocampi. Bifitose upregulated WWOX, and HAson8 significantly suppressed the AD-promoting pS14-WWOX in hippocampi. Notably, HAson8 significantly upregulated Sox2-positive neural stem cell in the subventricular zone, and parvalbumin expression interneurons in the hippocampi. HAson8 activated spleen Hyal-2+ Z lymphocytes, and that transfer of activated Z cells to recipient 3xTg enabled these mice to restore memory loss at month 9, suggesting that a novel immune cell lineage limits AD progression. Finally, HAson8/bifitose suppressed the population of AD-promoting Firmicutes and Bacteroidetes bacteria in the gut, and correlates with mitigation of AD progression in 3xTg mice. Together, HAson8 and bifitose are effective in mitigating AD progression in 3xTg mice via suppression of inflammatory glia cells, upregulation of Z cells and neural stem cells, and reducing AD-promoting gut bacteria.

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