以5×FAD模式鼠以及細胞模型探討天然物對阿茲海默氏症的神經保護作用

Abstract

阿茲海默氏症（Alzheimer’s disease, AD）是全球最常見之神經退化性疾病，病患的症狀為記憶喪失和認知行為的改變。AD的典型病理特徵包含：細胞外Aβ（amyloid-β）堆積形成類澱粉斑塊（amyloid plaques）、細胞內tau蛋白過度磷酸化導致神經纖維纏結（neurofibrillary tangles, NFT）、以及伴隨而來的神經發炎、氧化壓力最終導致神經元走向凋亡。本研究探討兩種天然來源物質分別為微生物發酵大豆粉（Fermented Soybean, FS）及Hedysarum alpinum多醣萃取物（HAP）於在阿茲海默症5×FAD小鼠模型中的神經保護潛力。動物行為結果顯示，長期口服FS或HAP可顯著改善5×FAD小鼠的短期與長期記憶缺損。後續機制探討發現FS可能經由調控Akt/GSK3β/Nrf2路徑使小鼠海馬迴中氧化酵素表現及抑制NF-κB訊號路徑抑制神經發炎反應，同時，FS能促進BDNF成熟及其下游突觸蛋白表現，減少Aβ堆積與神經膠質細胞活化，進而保護神經元存活。而HAP則可能透過降低Bace1表現減緩大腦中Aβ斑塊堆積，並可提升突觸功能蛋白NR2B表現，抑制GFAP、Iba-1等膠細胞增生指標及發炎相關基因iNOS、NLRP3、IL-1β、TNF-α等表現。此外，HAP具有改善腸道屏障完整性、抑制結腸組織中發炎細胞因子含量、以及增加如Lactobacillus等潛在益生菌的相對豐度之潛力。細胞實驗亦進一步證實HAP可有效抑制LPS誘導RAW264.7細胞發炎反應。綜合以上結果顯示FS以及HAP均具有改善阿茲海默氏症的神經保護潛力，並且FS源自於大豆製品製造過程中的副產物，可進一步提升產品的附加價值，減少製造過程中廢棄物的產生。Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by memory loss and cognitive decline. Pathologically, AD involves amyloid plaque accumulation, tau hyperphosphorylation forming neurofibrillary tangles, neuroinflammation, and oxidative stress, leading to neuronal death. This study evaluates the neuroprotective effects of fermented soybean (FS) and Hedysarum alpinum polysaccharide (HAP) in 5×FAD mice. Oral administration of FS or HAP significantly improved short-and long-term memory deficits. In addition, FS may modulate the Akt/GSK3β/Nrf2 pathway, enhancing antioxidant enzymes and suppressing NF-κB–mediated neuroinflammation, while promoting BDNF maturation and synaptic protein expression, reducing Aβ deposition and gliosis. HAP reduces Aβ plaques by downregulating Bace1, enhances synaptic NR2B, and inhibits glial markers GFAP, Iba-1, and inflammatory genes, including iNOS, NLRP3, IL-1β, and TNF-α. HAP also strengthens intestinal barrier function, reduces colon inflammation, and increases beneficial bacteria like Lactobacillus. In vitro, HAP suppresses LPS-induced inflammation in macrophages. These results suggest that FS and HAP have a potential neuroprotective effect in AD. Furthermore, as FS is a byproduct derived from the soybean fermentation process, its utilization could enhance the added value of soybean-based products while reducing waste generation during manufacturing.