探討第一介白素與NMDA受體於Aβ誘發阿茲海默氏症動物模型中所扮演的角色

Abstract

人口高齡化現在已經成為全球普遍的現象，阿茲海默症 (Alzheimer’s disease, AD) 的發病率伴隨著年齡的增長而急劇增加。阿茲海默症是一種漸進性神經退化疾病，會損害記憶力和認知障礙，目前缺乏對阿茲海默症病因的完全了解，所以透過動物的主動操作或使用轉基因動物模型來模擬疾病，進行相關研究。此外，研究已指出阿茲海默症病理特徵澱粉斑塊 (Amyloid-beta, Aβ) 和神經原纖維纏結 (Neurofibrillary tangles, NFT)，會促使發炎因子的釋放，例如發炎因子第一介白素 (Interleukin-1, IL-1β)，其為睡眠調節物質，睡眠也在Aβ的清除中也扮演了關鍵的角色，並影響阿茲海默症的病情。NMDA受體(N-methyl-D-aspartate receptor, NMDAR) 為谷氨酸受體，對於神經元的突觸可塑性和存活至關重要，被認為是學習和記憶的基礎，在臨床上與阿茲海默症患者中認知、記憶的逐步下降以及病理性神經解剖結構的發展相關。因此，本研究藉由注射不溶性的澱粉蛋白來誘導阿茲海默症，並探討第一介白素和NMDAR與阿茲海默症誘發之睡眠障礙之關係。 本研究使用腦室注射不溶性Aβ1-42以誘發阿茲海默症，並分析辨識以及空間記憶之行為。在免疫螢光染色上可以看到Aβ的累積，且注射Aβ1-42的組別運動能力都不佳，給予低劑量Aβ的組別辨識記憶也明顯受損；而空間記憶能力則沒有看出比較明顯的差異，此結果顯示腦室注射Aβ1-42確實會造成Aβ的累積以及辨識記憶能力下降。另一方面，經由Aβ注射後，NR2B亞單位在前額葉皮質則有顯著減少，初步結果表示阿茲海默症病理學會導致NMDAR下調。 總結以上，此研究結果顯示，利用腦室注射Aβ能誘發阿茲海默症的辨識記憶障礙，並且會影響NMDAR之活化。

Population aging has become a worldwide phenomenon. Alzheimer’s disease (AD) frequency increases strongly with age. AD is a progressive neurodegenerative disease that causes memory loss and cognitive impairment. Because the lack of full understanding of AD, simulating the disease with active operation of animals or using genetically modified animal models is commonly used to understand the pathophysiology. Evidence has demonstrated that the pathological markers of Alzheimer's disease, amyloid-beta (Aβ) deposition and neurofibrillary tangles (NFT), promote the release of pro-inflammatory cytokines, such as IL-1β. IL-1 is a sleep-regulating substance, and sleep plays a key role in the removal of Aβ and affects the progression of AD. NMDA receptor (N-methyl-D-aspartate receptor, NMDAR) is a high-density glutamate receptor and is essential for neurotransmission, neuronal synaptic plasticity and neuronal survival. NMDAR is considered to be the foundation of learning and memory which correlates clinically with the progressive decline in cognition/memory and the development of pathological neural anatomy seen in AD patients. Therefore, we studied induced-AD by injecting insoluble Aβ, and explored the relationship between interleukin-1 and NMDAR in Alzheimer's disease and AD-induced sleep disruption. In this study, the AD animal model was induced by Intracerebroventricular injection of insoluble amyloid Aβ1-42, the behaviors of identification and spatial memory were analyzed. We found that the poor locomotion activity was significant observed in the mice treated with Aβ1-42 than that treated with vehicle (NH4OH). Furthermore, the recognition memory was impairment in mice treated with Aβ1-42, but spatial memory was not altered. This result indicated the AD model caused a decline in the ability to recognize novel object and spatial memory. The expression of NR2 subunit protein of NMDAR in the prefrontal cortex was significantly lower in the mice treated with Aβ1-42. These findings suggest that amyloid-beta contributes to the down-regulation of NMDAR. In conclusion, our results indicated that the decrease of NMDAR activity by amyloid-beta may be the cause to impair memory.