IDENTIFICATION OF NOVEL APOE4 MODULATORS

Abstract

It is not clear to date if Apolipoprotein E4 (ApoE4), the major genetic risk factor in late onset Alzheimer's disease (AD), influences AD pathophysiology by a gain of toxic function or by a loss of protective function or a combination thereof. Three ApoE isoforms exist – ApoE2, ApoE3 and ApoE4 – that just differ in two amino acid sites. These amino acid substitutions are believed to alter ApoE structure and consequently physiology and be responsible for ApoE2's protective and ApoE4's detrimental effects (1, 2). The hypothesis that a structural difference between ApoE4 and ApoE3 (and ApoE2) is the cause of the ApoE4-associated increased risk for AD forms the basis of a novel therapeutic approach to modulate ApoE4 structure and turn it into an ApoE3-like molecule by using small molecule “structure correctors” (3). Such “structure correctors” or ApoE4 modulators have been described, however, these molecules lack good physico-chemical properties and were shown to be toxic in animal models. Consequently, well-validated tool compounds for evaluating the therapeutic potential of ApoE4 structural correctors are lacking. We developed a protocol for the purification of human ApoE4 and established a biophysical screen to identify novel compounds. Specifically, we used the Corning® Epic® label free platform and screened the NIH clinical collection (NCC) – a chemical library of small molecules that all have a history of use in human trials. Using the Corning® Epic® label free platform, we identified 13 compounds that interact with ApoE4. All compounds are drugs in clinical use of which a majority has CNS function. This is early screening data. Our “hit” molecules are currently being evaluated by alternative biophysical methods in the hope the confirmation and subsequent medicinal chemistry optimisation will result in the identification of novel tool compounds that can be used in future studies to investigate ApoE4 function.