Effects of bladder control medication on beta-amyloid peptide metabolism

描述(由申请人提供)：本提案的中心假设是不寻常的：膀胱排尿功能障碍与阿尔茨海默病(AD)和痴呆症相关。AD排尿问题的动物模型还没有研究过。用于治疗排尿问题的抗血吸虫药物以不可预测的方式影响A2代谢。这样做的风险是未知的，因为其影响的基础是未知的。这一假说源于已发表的和初步数据不一致的东莨菪碱和奥昔布宁的疗效。只要有信息，这两种化合物对淀粉样蛋白代谢的影响是一致的，但却是相反的。然而，这两种药物都是相对非特异性的M受体拮抗剂。在人脑和类似AD的Tg2576小鼠中，东莨菪碱增加了AD的病理改变。这只老鼠携带一种突变的APP(SWE)，导致家族性阿尔茨海默病。另一方面，奥施丁宁可以减少B6C3-TG(APPswe，PSEN1dE9)85dbo/J AD模型小鼠和携带AD线粒体的人神经母细胞瘤囊体的AD病理。来自JaxMice的B6C3TG是双转基因，突变的APP(SWE)和外显子9缺失的早老素1突变与家族性AD独立相关。药物的不同、PSEN1dE9基因的存在或包括胆碱能信号转导改变在内的多种原因的组合，都可能导致东莨菪碱和奥布替宁的相反作用。这项提案将验证痴呆相关排尿功能障碍的小鼠模型，并检查抗肌松药的影响。这项工作将解决以下问题：1)在两个品系的TGAD样鼠中，膀胱排尿功能障碍与AD脑病理之间是否存在关联？1B)东莨菪碱和奥昔布宁如何影响这种功能障碍？淀粉样变？1C)抗胆碱酯酶药物多奈齐平单独或与东莨菪碱或奥昔布宁联合应用，如何影响排尿功能障碍和淀粉样蛋白的形成？在体外？2B)胆碱能受体刺激是否改变反应？2C)急性和慢性效应是否不同？2D)分泌酶表达是否改变？3)TGAD样鼠和AD细胞系统中trkA和p75表达的变化是否与衰老和AD相似？4)受体亚型选择性药物与非选择性药物对A2产生的影响是否不同？4B)抗胆碱能药物的有害作用能被预防吗？这一结果将在新的动物模型中启动痴呆症相关排尿功能障碍的研究，并确定抗胆碱能药物对模型脑病理是有益还是有害影响。公共卫生相关性：这项研究将建立和验证与痴呆症相关的膀胱问题的小鼠模型，并确定用于老年人和阿尔茨海默病患者的膀胱控制药物是否会通过恶化脑结构损伤而使疾病恶化(S)。这项研究使用啮齿动物和细胞培养的疾病模型来测试药物的效果。

DESCRIPTION (provided by applicant): The central hypothesis of this proposal is unusual: Bladder voiding dysfunction associates with Alzheimer disease (AD) and dementia. Animal models of AD voiding problems have not been studied. Antimuscarinic agents, used to treat voiding problems, affect A2 metabolism in unpredictable ways. The risks of doing so are not known because the basis for the effects are not known. This hypothesis derives from inconsistencies in published and preliminary data on the effects of scopolamine vs. oxybutinin. Insofar as information is available, each of the two compounds affects amyloid metabolism consistently but oppositely. However, both drugs are relatively non-specific antagonists of muscarinic receptors. Scopolamine increases AD pathology in human brains and in the Tg2576 AD-like mouse. This mouse carries a mutated APP(swe) that causes a familial form of AD. Oxybutinin, on the other hand, reduces AD pathology in the B6C3-Tg (APPswe, PSEN1dE9)85dbo/J AD model mouse and in human neuroblastoma cybrids carrying AD mitochondria. The B6C3 Tg from JaxMice is a double transgenic, with the mutated APP(swe) and the exon 9 deleted presenilin 1 mutation independently associated with familial AD. The opposite effects of scopolamine and oxybutinin could derive from differences in the drugs, the presence of the PSEN1dE9 gene or a combination of causes including altered cholinergic signal transduction. This proposal will validate mouse models of dementia-associated voiding dysfunction and examine the impact of antimuscarinic medication. The work will address the following: 1a) Is there an association between bladder voiding dysfunction and AD brain pathology in the two strains of Tg AD-like mice? 1b) How do scopolamine and oxybutinin affect the dysfunction? Amyloidogenesis? 1c) How does the anticholinesterase drug donezepil affect voiding dysfunction and amyloidogenesis, alone or in combination with scopolamine or oxybutinin? 2a) How do scopolamine and oxybutinin affect A2 production in vivo? In vitro? 2b) Does cholinergic receptor stimulation alter responses? 2c) Are acute and chronic effects different? 2d) Is secretase expression altered? 3) Do Tg AD-like mice and AD cellular systems show changes in trk A and p75 expression similar to those found in aging and AD? Do anti-muscarinic agents affect the expression pattern? 4a) Do receptor sub-type selective agents differ from the less selective agents in effects on A2 production? 4b) Can deleterious effects of anticholinergic drugs be prevented? The results will initiate the study of dementia-associated voiding dysfunction in new animal models and determine if anticholinergic medications have beneficial or deleterious effects on model brain pathology. PUBLIC HEALTH RELEVANCE: This research will develop and validate mouse models of dementia-related bladder problems and determine if medications used for bladder control in the elderly and Alzheimer's disease patients might worsen the disease(s) by worsening brain structural damage. The study uses rodent and cell cultured disease models to test the effects of the medications.