Amyloid precursor protein mediated changes in intestinal epithelial phenotype in vitro

Area of Science:

• Gastroenterology
• Molecular Biology
• Cell Biology

Background:

• Amyloid precursor protein (APP) and its metabolites are primarily studied in the central nervous system.
• Limited information exists regarding the functions of APP and amyloid beta (Aβ) outside the brain, despite their presence in intestinal epithelial cells.

Purpose of the Study:

• To investigate the functional roles of APP and its metabolite Aβ in intestinal epithelial cells.
• To determine if APP influences cholesterol absorption and secretion processes.

Main Methods:

• Cultured human colonic epithelial cells (Caco-2) to analyze APP expression and Aβ secretion.
• Assessed Aβ uptake and cellular responses to Aβ and sAPP stimulation.
• Utilized co-immunoprecipitation (co-IP) to identify protein interactions, specifically with CD36 and FATP4.

Main Results:

• Caco-2 cells expressed APP and secreted Aβ 1-40 and Aβ 1-42, with LPS increasing Aβ 1-40 secretion.
• Aβ 1-40 stimulation increased IL-6 secretion and decreased cholesterol uptake, while sAPP-derived peptide increased cholesterol uptake.
• APP was found to associate with CD36, and APP stimulation modulated CD36-mediated cholesterol uptake.

Conclusions:

• APP forms a complex with CD36 in human colonic epithelial cells.
• Proteolytic fragments of APP, including sAPP and Aβ1-40, play reciprocal roles in regulating intestinal cholesterol uptake.
• These findings suggest APP is crucial for intestinal cholesterol homeostasis and may have broader biological implications.