阿茲海默氏症（Alzheimer’s disease）是一種好發在老年的神經退化性疾病，該疾病導致患者認知功能逐漸下降，其病理特徵包含細胞內神經纖維糾結，以及細胞外β-澱粉樣蛋白的沉積，這些沉積物會造成神經細胞死亡，並造成認知功能的受損。阿茲海默氏症的治療方式受到全球矚目，但目前仍無法有效的治癒該疾病，因此治療策略的開發極為迫切。薑黃素（Curcumin）是一種天然的化合物，其可通過血腦屏障（Blood-brain barrier），且具有抗發炎（anti-inflammation），以及抗氧化（anti-oxidant）的效果。有研究指出，薑黃素具有治療阿茲海默氏症的潛力，但因吸收效果不良及代謝過於迅速而展現出較差的生物可利用率，所以為了改善其生物可利用性，本研究使用不同的包裹材料以及修飾其官能基，進而提高其吸收率，探討薑黃素衍生物是否能減少腦中β-澱粉樣蛋白斑塊沉積及改善發炎反應。期盼本項研究可以提供阿茲海默氏症之新型治療策略，造福人群。首先，我們發現阿茲海默氏症疾病模式老鼠的認知行為缺陷，且在大腦中發現大量的β-澱粉樣蛋白斑塊的沉積，及高量的膠質細胞增生。後續利用餵食方式給予疾病模式老鼠傳統薑黃素以及薑黃衍生物持續四個月，發現薑黃衍生物可以改善疾病模式老鼠認知行為之缺陷。最終，發現在給予薑黃衍生物後，可能藉由微小膠細胞（microglia）改善β-澱粉樣蛋白斑塊的清除。總結，本篇論文發現在阿茲海默氏症中由β-澱粉樣蛋白斑塊大量沉積所引起的發炎情況，在利用薑黃衍生物的抗發炎能力後，成功的減緩大腦中發炎的現象，有效地減少β-澱粉樣蛋白斑塊、及恢復認知功能，並且提供可能的神經保護策略。

Alzheimer's disease (AD) is a common neurodegenerative disorder with a high prevalence in the elderly. It is characterized by progressive decline in cognitive function. The pathological hallmarks of AD include the presence of intracellular neurofibrillary tangles and extracellular beta-amyloid (Aβ) plaques that cause neuronal and synaptic loss in the brain. These depositions disrupt the interactions between neurons, cause cell death, and lead to impairment of cognitive function. Although AD therapy has garnered attention worldwide, a viable cure remains elusive and efficient treatment is still in urgent need. Curcumin is a natural compound that can penetrate the blood-brain barrier and has anti-inflammatory and anti-oxidant effects in animal models, implying the therapeutic potential of curcumin in the treatment of AD. However, curcumin exhibits poor bioavailability due to malabsorption and rapid metabolism. Therefore, new derivative compounds of curcumin were developed to improve its bioavailability. In this study, we investigated whether curcumin derivatives could reduce the level of Aβ and resolve the inflammation in a brain with AD. We expect this research to provide insights and discover a novel therapeutic strategy in AD treatment. First, we found that the triplex AD transgenic mice had cognitive dysfunction. A large amount of Aβ deposition and significant gliosis were present in the brain. We orally administered curcumin and its derivatives to the transgenic mice for 4 months and found that curcumin derivatives improved behaviour deficits in the AD mouse model. We identified that Aβ clearance through microglia was also improved after treatment with curcumin derivatives. In summary, we found that administration of curcumin derivatives can ameliorate gliosis in the transgenic mice, reduce the level of Aβ, and improve cognitive functions. We expect our findings to provide a potential neuroprotective strategy for AD.

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