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Updated: Apr 17, 2026
Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
Published on: October 17, 2015
Surface Trafficking of APP and BACE in Live Cells
Anna Bauereiss1, Oliver Welzel1, Jasmin Jung1
1Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany.
Abstract:
Amyloid-β (Aβ)-peptide, the major constituent of the plaques that develop during Alzheimer's disease, is generated via the cleavage of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE). Using live-cell imaging of APP and BACE labeled with pH-sensitive proteins, we could detect the release events of APP and BACE and their distinct kinetics. We provide kinetic evidence for the cleavage of APP by α-secretase on the cellular surface after exocytosis. Furthermore, simultaneous dual-color evanescent field illumination revealed that the two proteins are trafficked to the surface in separate compartments. Perturbing the membrane lipid composition resulted in a reduced frequency of exocytosis and affected BACE more strongly than APP. We propose that surface fusion frequency is a key factor regulating the aggregation of APP and BACE in the same membrane compartment and that this process can be modulated via pharmacological intervention.
Insights
Alzheimer's disease plaques involve Amyloid-β (Aβ) and APP-cleaving enzyme (BACE). This study reveals how these proteins traffic separately to cell surfaces, offering new targets for Alzheimer's disease therapies.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques.
- Aβ is generated from amyloid precursor protein (APP) by β-site APP-cleaving enzyme (BACE).
- Understanding the cellular dynamics of APP and BACE is crucial for AD pathogenesis.
Purpose of the Study:
- To investigate the live-cell kinetics and trafficking of APP and BACE.
- To elucidate the role of exocytosis and membrane composition in APP and BACE localization.
- To identify potential therapeutic targets for modulating Aβ production in AD.
Main Methods:
- Live-cell imaging using pH-sensitive fluorescent proteins to track APP and BACE.
- Simultaneous dual-color evanescent field illumination to observe protein co-localization.
- Perturbation of membrane lipid composition to assess its effect on protein trafficking.
Main Results:
- Distinct release kinetics were observed for APP and BACE.
- Evidence suggests APP cleavage by α-secretase occurs on the cell surface post-exocytosis.
- APP and BACE are trafficked to the cell surface in separate membrane compartments.
- Altering membrane lipid composition reduced exocytosis frequency, impacting BACE more than APP.
Conclusions:
- Surface exocytosis frequency is a key regulator of APP and BACE co-compartmentalization.
- Membrane lipid composition influences APP and BACE trafficking and interaction.
- Pharmacological modulation of these processes may offer therapeutic strategies for Alzheimer's disease.
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