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Tight control of the APP-Mint1 interaction in regulating amyloid production
Shawna M Henry1, Sabrina A Kistler1, Gavin D Lagani1
1Department of Biology, Boston University, Boston, MA, USA.
Abstract:
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.
Insights
Targeting the interaction between amyloid precursor protein (APP) and Mint1 adaptor proteins offers a potential Alzheimer's disease (AD) therapy. Modulating this interaction affects APP processing and Aβ generation.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) peptide generation from amyloid precursor protein (APP).
- The YENPTY motif on APP mediates its endocytosis, a crucial step in Aβ production.
- Cytosolic adaptor proteins called Mints bind to the YENPTY motif, influencing APP trafficking and processing.
Purpose of the Study:
- To investigate the role of the APP-Mint1 interaction in Aβ generation.
- To examine how specific Mint1 mutations affect APP and Mint1 cellular dynamics and interactions.
- To assess the therapeutic potential of targeting the APP-Mint1 interaction in Alzheimer's disease.
Main Methods:
- Generation and analysis of two Mint1 mutants: Mint1Y633A (enhanced APP binding) and Mint1Y549A/F610A (reduced APP binding).
- Investigation of cellular dynamics of APP and Mint1 in primary murine neurons.
- Assessment of Mint1's interaction with binding partners, including presenilin1.
Main Results:
- Mint1Y633A enhanced APP binding and APP endocytosis in neurons.
- Mint1Y549A/F610A reduced APP affinity and amyloid-beta (Aβ) secretion.
- The impact of Mint1Y549A/F610A on Aβ release was more significant than complete Mint protein knockdown, highlighting the interaction's critical role.
Conclusions:
- The interaction between APP and Mint1 is critical for Aβ production.
- Modulating the APP-Mint1 interaction can alter APP processing and Aβ generation.
- Targeting the APP-Mint1 interaction presents a promising therapeutic strategy for Alzheimer's disease.
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