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Updated: Jun 25, 2025

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
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Published on: October 17, 2015

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Small GTPases control macropinocytosis of amyloid precursor protein and cleavage to amyloid-β

Justin Chiu1,2, Jordan M Krupa3,2, Claudia Seah2

  • 1Department of Physiology and Pharmacology, The Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

Heliyon
|May 27, 2024
PubMed

Insights

Researchers identified key proteins, Rac1, Cdc42, and RhoA, involved in amyloid precursor protein (APP) internalization. Targeting these proteins reduces toxic amyloid-beta (Aβ) production, offering a potential therapeutic strategy for Alzheimer's disease.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Biochemistry

Background:

  • Alzheimer's disease (AD) is linked to amyloid-beta (Aβ) overproduction from amyloid precursor protein (APP).
  • APP cleavage and Aβ generation are proposed to occur after cell surface internalization.
  • A novel macropinocytosis pathway for APP internalization into lysosomes, leading to Aβ production, has been identified.

Purpose of the Study:

  • To investigate the roles of ADP-ribosylation factor 6 (Arf6) downstream effectors Rac1, Cdc42, and RhoA in APP internalization and Aβ production.
  • To determine if targeting these effectors can reduce Aβ generation.

Main Methods:

  • Pharmacological inhibition and siRNA knockdown of Rac1, Cdc42, and RhoA.
  • Assessment of APP colocalization with LAMP1-labeled lysosomes.
  • Measurement of Aβ40 and Aβ42 levels using ELISA.

Main Results:

  • Inhibition/knockdown of Rac1, Cdc42, and RhoA reduced APP colocalization with lysosomes.
  • APP transport to early endosomes was unaffected.
  • Significant decreases in Aβ40 and Aβ42 production were observed.

Conclusions:

  • Rac1, Cdc42, and RhoA are crucial components of the macropinocytosis pathway regulating APP internalization.
  • Targeting Rac1, Cdc42, and RhoA presents a potential therapeutic strategy to reduce Aβ production in Alzheimer's disease.
Keywords:
Alzheimer diseaseAmyloid precursor proteinLysosomesMacropinocytosisRhoGTPases

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