APP Induces AICD-Mediated Autophagy-Dependent Axon Degeneration

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Alzheimer's disease (AD) pathogenesis is linked to amyloid precursor protein (APP).
• The role of the APP intracellular domain (AICD) in AD is not well understood.
• Traditional focus has been on Amyloid beta (Aβ) production.

Purpose of the Study:

• To investigate the role of APP and AICD in axon degeneration.
• To establish a novel Drosophila model for studying AD-associated neurodegeneration.
• To identify mechanisms underlying APP/AICD-induced axon degeneration.

Main Methods:

• Expression of human APP in adult Drosophila wing margin neurons.
• Analysis of age-dependent axon degeneration.
• Investigating the role of autophagy and apoptosis.
• Identifying genetic pathways involved (FoxO/Snail-Atg1 axis).
• Testing the efficacy of chloroquine, an autophagy inhibitor.

Main Results:

• Ectopic APP expression induced age-dependent axon degeneration in Drosophila wings.
• AICD production was essential for APP-induced axon degeneration.
• AICD overexpression alone caused axon degeneration.
• Blocking autophagy, not apoptosis, alleviated degeneration.
• The FoxO/Snail-Atg1 axis mediated this process.
• Chloroquine treatment ameliorated APP/AICD-induced axon degeneration.

Conclusions:

• APP induces autophagy-dependent axon degeneration via AICD production.
• The FoxO/Snail-Atg1 pathway is crucial for this process.
• Autophagy inhibition represents a potential therapeutic strategy for AD.