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.
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. ? ? ?
