2026-11-092026-11-09https://scholars.csmu.edu.tw/handle/123456789/38816Alzheimer's disease (AD), the most widespread type of dementia, is a progressive neurogenerative disease caused by an accumulation of Aβ plaque deposits in the brains. Despite its high prevalence, the cause of AD is unknown, explaining the lack of effective medication for its treatment. For the time being, the apolipoprotein E4 (ApoE4) allele is the only well established genetic risk factor for late onset AD. Epidemiological studies suggest that disturbances in lipid homeostasis may contribute to the etiology of AD. Increasing evidence also suggests that interactions between CNS derived ApoE-associated lipid metabolism and Aβ homeostasis are critical in the etiology of AD. However, the mechanisms how ApoE and CNS lipid influences the onset and progression of AD remain incompletely understood. As the results, the present study will try to demonstrate a possible link among CNS lipids, ApoE, Aβ, and the incidence of AD. By using a cell line SK-N-MC conditional expression of C99, we have demonstrated in our preliminary data that ApoE-inhibited Aβ neuronal toxicity can be abolished by a cholesterol supplement. Based upon this finding, we will then clarify what the mechanism the overload CNS lipid increases Aβ-induced neurotoxicity, and evaluate how ApoE participated in these neurotoxic effects. Furthermore, it has been suggest that reduced AMP-activated protein kinase (AMPK) activities have been invoked to contribute to Aβ pathology. Since AMPK transmit pro-survival and protective signaling through lowering CNS lipid/cholesterol levels, it underlines a possible therapeutic use of AMPK-related pathways in AD. To confirm this hypothesis, we will test whether the chronic AMPK agonist treatments can decrease Aβ pathology in a high-fat-diet (HFD) Tg2576 Transgenic mice model. We hope our results further the notion of lipid-lowering effects in AMPK agonist will serve as a safe and effect prophylaxis for AD treatment.阿茲海默氏症(Alzheimer's disease, AD)是國內目前最常見的失智症，是由一種稱為乙型類澱粉(Aβ)的物質沈積在腦組織中而造成的神經性退化疾病。雖然阿茲海默氏症的罹患率相當高，但由於致病機轉尚不十分清楚，因此目前臨床上對此症也還沒有一種有效的治療方式。目前已知E4型脂載體蛋白(ApoE4)基因與此疾病的的發生率具有高度相關，而流行病學的研究也指出中樞神經系統中不正常的脂質代謝亦可能是阿茲海默氏症的成因之一。雖然許多證據皆指出E型脂載體蛋白可能參與著調控大腦中脂質與乙型類澱粉的代謝平衡過程，但其實際作用的機轉卻不甚明瞭。因此本計畫希望藉由研究中樞神經系統中的E型脂載體蛋白、脂質代謝與乙型類澱粉之間的關係，來探究阿茲海默氏症的確實發病機制。利用條件表現之轉殖乙型類澱粉前驅物(APP)C99片段神經細胞株SK-N-MC，初步的研究結果顯示細胞中的E型脂載體蛋白可以有效的降低乙型類澱粉所造成的細胞毒性，而這種保護作用卻會被膽固醇所抑制，據此我們將基於這個現象，進一步釐清在中樞神經系統中過量的脂質如何更進一步的惡化乙型類澱粉所造成的神經毒性，同時E型脂載體蛋白在這其中究竟扮演著何種角色。除此之外，先前相關的研究亦指出過低的腺苷單磷酸活化激酶(AMPK)的活性與阿茲海默氏症的致病過程有關，既然單磷酸活化激酶被認為可經由降低中樞神經系統中的脂質/膽固醇含量來達到保護神經細胞的作用，因此邏輯上應該適合作為阿茲海默氏症的治療標的。為了證實這個想法，我們將利用高脂質食物餵食Tg2576轉殖基因小鼠的方式，長時間給予單磷酸活化激酶活化物，來測試是否能有效的抑制高脂質所加重的阿茲海默氏症致病過程。我們希望能夠經由此研究計畫，證明促進單磷酸活化激酶活性所導致的降脂質作用可以有效降低阿茲海默氏症的症狀，並提供一新路徑使得將來可以利用單磷酸活化激酶作為標的，發展出一種新的阿茲海默氏症之治療方式。阿茲海默氏症類澱粉前驅蛋白乙型類澱粉蛋白E型脂載體蛋白腺苷單磷酸活化激酶Alzheimer's diseaseamyloid precursor proteinβ-amyloidapolipoprotein EAMP-activated protein kinaseProject