探討咖啡酸透過促進海馬迴神經新生改善糖尿性認知障礙之效益

糖尿病是一種慢性代謝性疾病，其中90%的患者為第二型糖尿病(type 2 diabetes mellitus, T2DM)，其典型特徵為長期的高血糖、胰島素阻抗與慢性發炎，也是造成糖尿病併發症的主要原因。雖然認知障礙在所有糖尿病併發症中相對較少被研究，但因其罹患風險高，且後續可能再進一步發展為神經退化疾病 (neurodegenerative disease, ND)，將嚴重影響患者的生活品質並造成醫療與社會經濟龐大的負擔。因此，在糖尿病神患者中，認知障礙的診斷、預防和治療已變得由為重要。海馬迴是大腦中主管記憶和學習的主要區域，動物成年後大腦仍持續生成新神經元的現象，稱為成人海馬迴神經新生(adult hippocampal neurogenesis, AHN)。近年研究指出，健康受試者中AHN現象較為普遍，但ND患者中則大幅減少，由此促進AHN可能是治療認知障礙的潛力策略。咖啡酸 (caffeic acid, CA) 為一種廣泛存在各種植物中的多酚類化合物，已被證實具有抗氧化、抗發炎與減輕腦部疾病等功效。本研究旨在探討CA是否能經由促進AHN來阻斷發炎及減少氧化壓力，進而預防與改善糖尿病性認知障礙。動物實驗中，透過施打鏈脲佐菌素 (Streptozotocin, STZ) 搭配高脂飲食加速ApoE-/-小鼠產生糖尿病性認知障礙，並同步管餵CA觀察其保護效果。實驗透過Y迷宮測試小鼠記憶與空間能力，並利用IHC觀察AHN與氧化相關蛋白的表現量；結果發現，CA介入後提升糖尿病性認知障礙小鼠空間記憶能力和AHN相關蛋白 (DCX、NeuN等) 表現量。細胞實驗中，以CA預處理HT-22小鼠海馬迴細胞，再以高糖、油酸誘導產生神經損傷，以觀察CA預防糖脂毒性造成細胞退化和促神經突觸生長的效果。結果觀察到CA介入的組別不僅保護神經突觸免受氧化損傷，也發現促神經突觸可塑性、抗氧化以及促細胞增生路徑相關指標蛋白表現量增加，同時神經發炎、凋亡與阿茲海默症相關蛋白表現量下降。綜合以上實驗結果，說明CA能夠經由促進AHN來阻斷神經發炎及減少氧化壓力，證明其在預防與改善糖尿病性認知功能障礙方面具有潛力。

Diabetes mellitus is a chronic metabolic disease, with type 2 diabetes mellitus (T2DM) accounting for 90% of cases. It is characterized by prolonged hyperglycemia, insulin resistance, and chronic inflammation, which are also the primary causes of diabetes-related complications. Although cognitive impairment is relatively less studied among diabetes complications, its high incidence and potential progression to neurodegenerative diseases significantly impact patients' quality of life and impose substantial healthcare and socioeconomic burdens. Consequently, the diagnosis, prevention, and treatment of cognitive impairment in diabetic patients have become increasingly important. The hippocampus, a key brain region responsible for memory and learning, continues to generate new neurons in adulthood, a phenomenon known as adult hippocampal neurogenesis (AHN). Recent studies have shown that AHN is prevalent in healthy individuals but significantly reduced in neurodegenerative disease (ND) patients. Therefore, promoting AHN may be a potential strategy for treating cognitive impairment. Caffeic acid (CA), a polyphenolic compound widely present in various plants, has been shown to possess antioxidant, anti-inflammatory, and neuroprotective effects. This study aims to investigate whether CA can prevent and improve diabetic cognitive impairment by promoting AHN, blocking inflammation, and reducing oxidative stress. In the animal experiment, diabetes-induced cognitive impairment in ApoE-/- mice was accelerated by Streptozotocin (STZ) injection and a high-fat diet, with simultaneous oral administration of CA to observe its protective effects. The Y-maze test was used to evaluate the mice's memory and spatial abilities, and immunohistochemistry (IHC) was utilized to observe the expression levels of AHN and oxidative stress-related proteins. The results indicated that CA intervention improved spatial memory and increased the expression of AHN-related proteins in diabetic cognitive impairment mice. In the cell experiment, HT-22 mouse hippocampal cells were pretreated with CA, followed by induction with high glucose and oleic acid to simulate neurotoxicity. The effects of CA on preventing glucolipotoxicity-induced cell degeneration and promoting synaptic growth were observed. The results showed that CA intervention not only protected synapses from oxidative apoptosis but also increased the expression of proteins related to synaptic plasticity, antioxidant activity, and BDNF pathways, while reducing the expression of neuroinflammation, apoptosis, and Alzheimer's disease-related proteins. In summary, the experimental results demonstrate that CA can block neuroinflammation and reduce oxidative stress by promoting AHN, indicating its potential in preventing and improving diabetic cognitive impairment.