Development of Novel APP Dimerization Inhibitors That Lower Abeta Levels

Year 2 aims:

Diseases that affect learning and memory are of fundamental biological importance and are among the most challenging biomedical problems of our time. We recently demonstrated that compounds that inhibit amyloid precursor protein (APP) dimerization and enhance APP phosphorylation reduce the levels of Abeta, the peptide responsible for the neurotoxicity seen in Alzheimer’s disease. In this project, we are further studying the mechanism of action and therapeutic potential for inhibitors of the proteins involved in the phosphorylation of APP and reduction of Abeta, and expect that results obtained from this study will produce candidate molecules for future studies aimed at reducing Abeta in vivo and in clinical trials of Alzheimer’s patients.

Year 1 aims:

Globally, people are living longer, and Alzheimer’s disease (AD), the major form of dementia among the elderly, is reaching pandemic proportions. Cognitive functions such as learning and memory are of fundamental biological importance, and diseases that affect these functions are among the most challenging biomedical problems of our time scientifically, emotionally and financially. Moreover, after decades of intense research and billions of dollars spent on clinical trials, no disease-modifying treatment for AD has been identified. In AD, amyloid beta peptides (Abeta) accumulate in the brain and have toxic effects on neurons and their synapses. Here we propose a novel strategy that intends to lower Abeta and its associated toxicity by inhibiting the amyloid precursor protein (APP) dimerization and phosphorylation process involving the receptor tyrosine kinase c-Kit. Moreover, c-Kit is found in a complex with Gab2, a gene previously identified in genomewide association studies to be associated with AD.

Our specific aims are to: 1) further characterize the mechanism linking c-Kit inhibition to inhibition of APP dimerization, enhancement of APP phosphorylation and the lowering of Abeta, and 2) optimize and characterize in vitro the lead Y series of Abeta-lowering compounds to prepare chemical probes with optimal pharmacokinetic and central nervous system exposure properties. These small molecules could become novel treatments for AD by reducing the levels of Abeta before the peptide exerts its toxic effects, thereby protecting neurons, their synapses and other cells impacted by Abeta.