2015-08-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/668585摘要：阿茲海默氏症為失智症中最常見的病因，乙型類澱粉堆積而成的類澱粉蛋白質斑塊是 此病腦部之重要表現。乙型類澱粉於腦部之堆積量取決於其形成與移除之間的平衡關係。 移除乙型類澱粉主要需依賴類澱粉移除蛋白及腎臟功能。先前之研究證實慢性腎病患者之 血清中乙型類澱粉濃度比非腎病患者高，且透析治療可有效降低血清中乙型類澱粉濃度。 然而，究竟慢性腎病是否會加速腦部類澱粉沈積並加速惡化阿茲海默氏症的認知功能障礙 仍舊未知。本計畫假設慢性腎病會藉由加速乙型類澱粉堆積於腦部而加速阿茲海默氏症之 惡化。研究方法：基礎研究的部分，我們將在野生型（C57BL/6)及三重突變阿茲海默轉殖鼠（3xTg-AD)各別取 9、12、15個月大之個體，兩品種實驗鼠各有一半之小鼠進行5/6腎臟移除手術以達到慢 性腎病，另一半之小鼠則接受sham-operation。再以新物再認測驗以及Y-迷宮測驗來測 試小鼠於慢性腎病前/後1、3個月及5個月之記憶功能。之後以腦部類澱粉正子攝影分析 腦部各個區域之類澱粉堆積情形，再以免疫螢光染色及西方點墨法定量腦部不同區域的類 澱粉及tau蛋白沈積量，以及與類澱粉生成及降解有關的蛋白活性變化（如P-secretase, y-secretase, mitogen-activated protein kinase, neprilysin 等）。在臨床研究的部分，我們將納入輕度阿茲海默氏症患者同時合併或無慢性腎病各30位。 神經心理測驗，血清類澱粉(AP40, AP42)及tau蛋白濃度以及腦部類澱粉正子攝影等，將 會在收案當下、六個月及一年時進行檢查。二年計畫預期進度：第一年：1-1:開始進行野生型及三重突變阿茲海默轉殖鼠的慢性腎病與式，進行記憶行 為測驗、腦部類澱粉正子攝影並收集腦組織。1-2 ：開始招募輕度阿茲海默氏症患者同時 合併或無慢性腎病，並安排各項檢查。第二年：2-1:開始分析腦組織不同區域的類澱粉及tau蛋白沈積及相關的製造與分解類 澱粉沈積的蛋白及酵素活性。2-2:完成臨床的個案收集及各項檢查（預期每組個案數約 30人），並分析比較臨床各組的資料。本研究計晝預期可以提供慢性腎病在阿茲海默氏症類澱粉沈積及認知能力下降的重要嶄 新角色。<br> Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. Amyloid plaques, composed of aggregations of amyloid-P (AP), are the hallmark brain lesions of AD patients. Ap levels in the brain are controlled by a dynamic equilibrium between its production from the amyloid precursor protein and removal. The removal depends on amyloid clearance proteins and renal function. Previous studies documented that the serum AP level increased in chronic kidney disease (CKD) patients and decreased after dialysis. However, whether CKD plays a role in the acceleration of deposition of Ap and hastens the progression of AD remains uncertain. We hypothesize that CKD accelerate the progression of AD through enhanced deposition of Ap and tau proteins.Methods: In basic part, we will use 3xTg-AD mice for AD model and wild type C57BL/6 mice at 9, 12 and 15 months old. Half of the mice in each strains will receive 5/6 nephrectomy surgery to achieve CKD state, and another half will receive sham-operation. Novel object recognition test and Y-maze spontaneous alternation test will be tested for memory at baseline and after CKD 1, 3 and 5 months. Amyloid positron emission tomography (PET) will be used to evaluate amyloid deposition in the brain. Quantification of amyloid and tau burden at different brain regions and candidate proteins related to amyloid generation or degradation will be analyzed by immunofluorescence staining and western blot.In clinical part, we will recruit early-stage AD patients with and without moderate CKD, and the number will be 30 in each group. Neuropsychological test, serum Ap40, Ap42 peptides and tau protein levels, and amyloid PET will be checked at baseline, 6 months and 12 months after recruitment.Schedule for this 2-year project:First Year. 1-1: Wild type and 3xTg-AD mice will receive CKD surgery. Amyloid PET and brain tissue will be harvested at 1, 3 and 5 months after CKD. 1-2: Recruit AD patients with/without moderate CKD, arrange neuropsychological test, serum Ap levels, and amyloid PET.Second year. 2-1: Start analysis of amyloid and tau burdens at different brain regions and associated proteins. 2-2: Complete clinical recruitment and evaluation.Our study will be anticipated to reveal the influence of CKD on amyloid deposition and cognitive impairment in AD patients.類澱粉阿茲海默氏症失智症慢性腎病amyloidAlzheimers diseasedementiachronic kidney disease