Understanding the Neuroprotective Activities of Posiphen

Medical University Of South Carolina, Charleston SC

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Abstract

DESCRIPTION (provided by applicant): Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) neuropathology early in life, and develop progressive cognitive impairment in their fourth or fifth decade. Transgenic mice expressing Amyloid beta protein (A¿) precursor (APP) deposit amyloid but do not present degeneration phenotypes. A mouse model of DS, the Ts65Dn mice, suffers degeneration of a number of neuronal subtypes, including the basal forebrain cholinergic neurons that are lost in AD. This appears to require APP duplication although high APP is not sufficient to induce neurodegeneration in transgenic mice. We previously identified a novel compound - Posiphen - that inhibits APP translation by regulating the 5'-untranslated region of APP. We are planning to reduce APP expression by treating animal models with Posiphen to determine whether long-term treatment could arrent AD like pathology and if neurodegeneration in DS can be prevented by this treatment. The neurodegeneration in the TS65Dn mice appears to depend on APP making it a useful model to evaluate neuroprotection by anti-APP therapies. This R21 project will test the hypothesis that reduction of APP synthesis will restore homeostasis of this highly expressed protein and therefore prevent neuronal loss and behavior in DS mice. The second hypothesis is that Posiphen treatment will reduce amyloid accumulation as plaques. In future studies, we plan to continue collaborating with Dr. Nigel Greig for clinical development of the drug. The two specific aims of the project are: 1) Evaluate the effects of Posiphen treatment in the TS65Dn mice, which naturally express 1.5 times higher levels of APP and accumulate secreted APP derivatives with age; 2) Determine the effect of Posiphen on amyloid deposition in transgenic mouse models. We hypothesize that the treatment will successfully reduce neurodegeneration in the DS mouse model and provide us with the tools to identify the late and windows that may be targeted for intervention.