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）和痴呆有关。AD排尿问题的动物模型尚未研究。抗毒蕈碱类药物，用于治疗排尿问题，以不可预测的方式影响A2代谢。这样做的风险尚不清楚，因为影响的基础尚不清楚。这一假设源于关于东莨菪碱与奥布丁碱作用的已发表和初步数据的不一致。就现有信息而言，这两种化合物中的每一种都对淀粉样蛋白代谢产生一致但相反的影响。然而，这两种药物都是相对非特异性的毒蕈碱受体拮抗剂。东莨菪碱增加了人类大脑和Tg2576 AD样小鼠的AD病理。这只老鼠携带一种突变的APP(swe)，它会导致家族性AD。另一方面，Oxybutinin在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细胞系中降低AD病理。来自JaxMice的B6C3 Tg是双转基因的，突变的APP（swe）和9外显子缺失的早老素1突变与家族性AD独立相关。东莨菪碱和oxybutinin的相反作用可能源于药物的差异，PSEN1dE9基因的存在或包括改变的胆碱能信号转导在内的多种原因的组合。该建议将验证痴呆相关排尿功能障碍的小鼠模型，并检查抗毒蕈碱药物的影响。这项工作将解决以下问题：1a)在两种Tg AD样小鼠中，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oxybutinin如何影响功能障碍？Amyloidogenesis吗?1c)抗胆碱酯酶药物多奈匹尔单独或与东莨菪碱或奥布丁苷合用对排尿功能障碍和淀粉样蛋白形成有何影响？2a)东莨菪碱和oxybutinin如何影响体内A2的产生？体外?2b)胆碱能受体刺激会改变反应吗？急性和慢性影响不同吗？2d)分泌酶表达是否改变？3) Tg AD样小鼠和AD细胞系统是否显示trk A和p75表达的变化与衰老和AD中发现的相似？抗毒蕈碱药物是否影响表达模式？受体亚型选择性药物对A2产生的影响与选择性较低的药物不同吗？4b)抗胆碱能药物的有害作用是否可以预防？该结果将在新的动物模型中启动与痴呆相关的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否有有益或有害的影响。公共卫生相关性：本研究将开发和验证痴呆症相关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膀胱控制的药物是否可能通过加重脑结构损伤而使疾病恶化。该研究使用啮齿动物和细胞培养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.