This project is designed to obtain biochemical support for developing treatments that prevent amyloid deposition in brains of AD patients. The overall goal of this project is to determine whether a pharmacological treatment affects levels of amyloid precursor protein (APP) derivatives in blood or cerebrospinal fluid (CSF) of patients with AD. The specific APP fragments are the N-terminal moities (APPs) and soluble Ab1-40 and Ab1-42. The pharmacological treatment is the investigational drug AF102B, which is a selective m1 receptor cholinergic agonist. The specific hypothesis is that AF102B administration will increase levels of APPs, and decrease levels of Ab1-42. Amyloid depositionis an early event in AD and characterizes much of its histopathology. Filmentous deposits of amyloid occur in the cortical neuropil as senile plaques Ab1-40 as congophilic angiopathy in AD. In some experimental systems, amyloid has neurotoxic effects which apparently derive from the intact Ab transmembrane fragment of a large amyloid precursor protein (APP). In most cases of AD, amyloid in AD is formed in the brain because of changes in proteolytic APP processing and not because of altered genetic or molecular properties. As information accrues regarding factors that influence APP processing, it should be possible to develop pharmacological treatments designed to decrease Ab deposition. If Ab deposition is an initiating event in causing neurotoxicity, then blocking Ab would be expected to prevent neuronal degeneration, and stop the evolution of dementia.
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