The transmembrane domain of APP (APPTM) contains the γ-secretase cleavage sites for the release of Aβ, which aggregates to form amyloid plaque, a pathologic hallmark of Alzheimer’s disease (AD). FAD mutations within APPTM can cause familial Alzheimer’s disease (FAD) by raising Aβ42/Aβ40 ratio. We solved the solution NMR structures of APPTM, in both WT and V44M FAD-mutant forms and showed that FAD mutations can increase the conformational dynamics of a crucial site, T48, for enhancing Aβ42 production. We also probed the interaction of APPTM with presenilin homologs (PSH) and found that substrate docking in intramembrane proteolysis is mediated by juxtamembrane lysines, coupled with helical unwinding. We have found that covalent and non-covalently interactions with juxtamembrane lysines can inhibit intramembrane proteolysis of APPTM by both PSH and γ-secretase. Using a DNA-encoded compound library (DEL), we have discovered a novel inhibitor of gamma-secretase cleavage with IC50 of ~0.1 μM. These data suggest that APPTM, the substrate of γ-secretase, can be a novel and viable target for AD drug discovery.  

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Faculty Host: Jianhan Chen
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