Development of Novel Therapies for AD Targeting Abeta Clearance

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging, with one in eight older Americans diagnosed with AD. It is also the most frequently diagnosed type of dementia within the Veterans Affairs (VA) Medical System, and one of the major causes of morbidity and mortality among veterans. The Department of VA estimates that 600,000 veterans suffered from severe AD and other forms of dementia in 2000, and this number is increased significantly today, because of the increasing proportion of older veterans and the increased prevalence of dementia in veterans that suffer from traumatic brain injury (TBI) and/or post- traumatic stress disorder (PTSD). Therefore, AD research studies are particularly important to veterans. Currently no treatment is available to slow or stop AD. There is great need for identification of more efficacious therapies for AD, which is among the priorities of VA RR&D research directions. Synaptojanin 1 (synj1), the main phosphoinositol (4,5) biphosphate phosphatase [PI(4,5)P2 degrading enzyme] in the brain and synapses, has been recently linked to AD. More importantly, we have characterized a NOVEL mechanism by which synj1 regulates cellular clearance of A¿. Down-regulation of synj1 promotes A¿ uptake and lysosomal trafficking, and thereby facilitates cellular A¿ clearance. Subsequently, reduction of synj1 attenuates amyloid induced neuropathologic changes and behavior deficits in an AD transgenic mouse model. Our findings suggest that reduction of synj1 has potential benefits for AD. Based on these studies, we performed a preliminary screening of a library of compounds (total ~3,600 small molecules) with the potential to reduce synj1 protein levels using "The Connectivity Map". We selected 89 small molecules (top hits) for further study and found 10 lead compounds with synj1/A¿-lowering effects in wild-type primary neuron cultures. Preliminary studies showed one calcium channel blocker nimodipine but not nifedipine, reduces both synj1 and A¿ levels in a dose-dependent manner with good dose-effect correlation. Further administration of nimodipine for one month, is capable of reducing brain content of synj1/A¿, as well as improving cognitive functions in an AD transgenic mouse model. In this application, we propose to characterize the mechanism of action for lead compounds exhibiting synj1/A¿ lowering effects (aim 1: Mechanistic Studies), and to evaluate the ability of selected lead compounds to reduce A¿-induced neuropathology and cognitive dysfunction in an AD transgenic mouse model (aim 2: Proof of Concept). Knowledge gained from this application will provide the foundation for designing a full-scale project exploring bioavailability, pharmacokinetics and toxicological characteristics of lead compounds for AD therapy. Taken together, the proposed studies have significant clinical relevance and scientific importance. Information obtained from our studies wil advance our knowledge in developing more potent AD therapies, directly benefits Veterans populations, and improves the quality of service provided within the VA health care system.