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F-spondin interaction with the apolipoprotein E receptor ApoEr2 affects processing of amyloid precursor protein

Hyang-Sook Hoe1, David Wessner, Uwe Beffert

  • 1Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20057-1464, USA.

Molecular and Cellular Biology
|October 18, 2005
PubMed

Insights

F-spondin, an extracellular matrix protein, interacts with amyloid precursor protein (APP) and its receptor ApoEr2. This interaction influences APP processing, reducing amyloid-beta (Abeta) production and potentially impacting Alzheimer's disease pathology.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • F-spondin is an extracellular matrix protein.
  • Amyloid precursor protein (APP) processing is crucial in Alzheimer's disease.
  • Apolipoprotein E receptor 2 (ApoEr2) is involved in neuronal function.

Purpose of the Study:

  • To investigate the interaction between F-spondin and APP.
  • To determine if F-spondin interacts with apoE receptors.
  • To elucidate the role of F-spondin-ApoEr2 interaction in APP processing and Abeta production.

Main Methods:

  • Coimmunoprecipitation experiments to detect protein interactions.
  • Transfection of cells and primary neurons with F-spondin and APP constructs.
  • Analysis of APP and ApoEr2 cleavage products and surface expression.
  • Inhibition studies using receptor-associated protein (RAP).

Main Results:

  • F-spondin directly interacts with ApoEr2 via its thrombospondin domain.
  • F-spondin increases the co-clustering and surface expression of APP and ApoEr2.
  • Full-length F-spondin promotes APP and ApoEr2 cleavage but decreases beta-CTF production and Abeta generation.
  • Receptor-associated protein (RAP) blocks the reduction in APP beta-CTF, confirming ApoEr2's role.

Conclusions:

  • F-spondin acts as a molecular bridge, clustering APP and ApoEr2 on the cell surface.
  • This clustering alters APP and ApoEr2 processing, leading to reduced amyloid-beta production.
  • The findings suggest a novel mechanism involving extracellular matrix proteins in regulating APP metabolism, with implications for Alzheimer's disease research.

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