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Related Experiment Video

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APP-BACE1 Interaction and Intracellular Localization Regulate Aβ Production in iPSC-Derived Cortical Neurons.

Sandra Roselli1, Tugce Munise Satir2, Rafael Camacho3

  • 1Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Blå Stråket 15, Sahlgrenska Hospital, 405 30, Gothenburg, Sweden. sandra.roselli@gu.se.

Cellular and Molecular Neurobiology
|June 24, 2023
PubMed
Summary

Investigating amyloid precursor protein (APP) interactions with secretases in Alzheimer's disease models reveals that APP proximity to BACE1 and PSEN1 regulates amyloid-beta production. Targeting these interactions may offer a novel therapeutic strategy for Alzheimer's disease.

Keywords:
Amyloid betaAmyloid precursor proteinBeta secretaseEarly endosomesGamma secretaseNeuronsProximity ligation assay

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Alzheimer's disease (AD) is pathologically defined by amyloid-beta (Aβ) plaques.
  • Amyloid precursor protein (APP) processing by β- and γ-secretase is central to Aβ generation and AD research.
  • The precise influence of APP-secretase physical interactions on APP processing remains incompletely understood.

Purpose of the Study:

  • To investigate the relationship between APP processing and the subcellular proximity of APP to β- and γ-secretase.
  • To compare Aβ production and APP-secretase interactions in low Aβ-secreting neuroprogenitor cells (NPCs) versus high Aβ-secreting mature neurons derived from human induced pluripotent stem cells (iPSCs).

Main Methods:

  • Utilized genetically identical human iPSC-derived NPCs and mature neurons as models for low and high Aβ production, respectively.
  • Quantified levels of APP, secretase enzymes (BACE1, PSEN1), and processing products (sAPPβ, CTFs).
  • Assessed the colocalization of APP species with secretases within endo-lysosomal organelles.

Main Results:

  • Mature neurons showed increased colocalization of full-length APP (flAPP) with BACE1 in early endosomes, correlating with elevated sAPPβ levels.
  • Neurons exhibited greater colocalization of APP C-terminal fragments (CTFs) with PSEN1 compared to NPCs.
  • In NPCs, APP-CTF interaction with BACE1 was more prominent than flAPP/BACE1 interaction, suggesting potential product-enzyme inhibition.

Conclusions:

  • APP and its cleavage product interactions with secretases positively and negatively regulate Aβ production.
  • The physical proximity and localization of APP species to secretases are critical determinants of amyloidogenic processing.
  • Targeting APP-secretase interactions, rather than secretases directly, presents a promising novel therapeutic avenue for Alzheimer's disease due to the enzymes' ubiquitous roles.