Tight control of the APP-Mint1 interaction in regulating amyloid production

Generation of amyloid-beta (Aβ) peptides through the proteolytic processing of the amyloid precursor protein (APP) is one pathogenic event in Alzheimer’s disease (AD). APP is a type I transmembrane protein and endocytosis of APP mediated by the endocytic YENPTY sequence is a key step in Aβ generation. We and others have found that Mints, a family of cytosolic adaptor proteins, directly binds to the YENPTY motif of APP via phosphotyrosine binding (PTB) domain of Mints, facilitates APP trafficking and processing. We also show mutation of Tyr633 of Mint1 (Mint1 Y633A ) enhances APP binding and processing. Now, we created a low-affinity Mint1 mutant that targets two conserved residues, Tyr549 and Phe610 (Mint1 Y549A/F610A ), that reduced APP binding. Here, we investigate how perturbing the APP-Mint1 interaction alters APP and Mint1 cellular dynamics as well as Mint1’s interaction with its other binding partners. We show that Mint1 Y633A increased binding affinity specifically for APP and presenilin1, enhanced APP endocytosis, and Aβ secretion in primary neurons. Conversely, Mint1 Y549A/F610A exhibited reduced APP affinity and Aβ secretion. In fact, the effect of Mint1 Y549A/F610A on Aβ release was greater compared to knocking down all three Mint proteins, supporting targeting APP-Mint1 interaction as a potential AD therapeutic.