TY - JOUR

T1 - Tight control of the APP-Mint1 interaction in regulating amyloid production

AU - Henry, Shawna M.

AU - Kistler, Sabrina A.

AU - Lagani, Gavin D.

AU - Bartling, Christian R.O.

AU - Özcelik, Dennis

AU - Sereikaite, Vita

AU - Strømgaard, Kristian

AU - Beffert, Uwe

AU - Ho, Angela

N1 - Publisher Copyright: © 2023 The Author(s)

PY - 2023

Y1 - 2023

N2 - Generation of amyloid-β (Aβ) peptides through the proteolytic processing of the amyloid precursor protein (APP) is a pathogenic event in Alzheimer's disease (AD). APP is a transmembrane protein and endocytosis of APP mediated by the YENPTY motif is a key step in Aβ generation. Mints, a family of cytosolic adaptor proteins, directly bind to the YENPTY motif of APP and facilitate APP trafficking and processing. Here, we generated and examined two Mint1 mutants, Tyr633Ala of Mint1 (Mint1Y633A) that enhanced APP binding, and Tyr549Ala and Phe610Ala mutant (Mint1Y549A/F610A), that reduced APP binding. We investigated how perturbing the APP-Mint1 interaction through these Mint1 mutants alter APP and Mint1 cellular dynamics and Mint1′s interaction with its other binding partners. We found that Mint1Y633A increased binding affinity specifically for APP and presenilin1 (catalytic subunit of γ-secretase), that subsequently enhanced APP endocytosis in primary murine neurons. Conversely, Mint1Y549A/F610A exhibited reduced APP affinity and Aβ secretion. The effect of Mint1Y549A/F610A on Aβ release was greater compared to knocking down all three Mint proteins supporting the APP-Mint1 interaction is a critical factor in Aβ production. Altogether, this study highlights the potential of targeting the APP-Mint1 interaction as a therapeutic strategy for AD.

AB - Generation of amyloid-β (Aβ) peptides through the proteolytic processing of the amyloid precursor protein (APP) is a pathogenic event in Alzheimer's disease (AD). APP is a transmembrane protein and endocytosis of APP mediated by the YENPTY motif is a key step in Aβ generation. Mints, a family of cytosolic adaptor proteins, directly bind to the YENPTY motif of APP and facilitate APP trafficking and processing. Here, we generated and examined two Mint1 mutants, Tyr633Ala of Mint1 (Mint1Y633A) that enhanced APP binding, and Tyr549Ala and Phe610Ala mutant (Mint1Y549A/F610A), that reduced APP binding. We investigated how perturbing the APP-Mint1 interaction through these Mint1 mutants alter APP and Mint1 cellular dynamics and Mint1′s interaction with its other binding partners. We found that Mint1Y633A increased binding affinity specifically for APP and presenilin1 (catalytic subunit of γ-secretase), that subsequently enhanced APP endocytosis in primary murine neurons. Conversely, Mint1Y549A/F610A exhibited reduced APP affinity and Aβ secretion. The effect of Mint1Y549A/F610A on Aβ release was greater compared to knocking down all three Mint proteins supporting the APP-Mint1 interaction is a critical factor in Aβ production. Altogether, this study highlights the potential of targeting the APP-Mint1 interaction as a therapeutic strategy for AD.

KW - Alzheimer's disease

KW - Amyloid

KW - APP

KW - Mint1

U2 - 10.1016/j.brainres.2023.148496

DO - 10.1016/j.brainres.2023.148496

M3 - Journal article

C2 - 37499733

AN - SCOPUS:85165867565

VL - 1817

JO - Brain Research

JF - Brain Research

SN - 0006-8993

M1 - 148496

ER -