APP binds DR6 to trigger axon pruning and neuron death via distinct caspases

Area of Science:

• Neuroscience
• Molecular Biology
• Developmental Biology

Background:

• Axonal pruning and neuronal cell death are critical for neural development but their mechanisms are unclear.
• Beta-amyloid precursor protein (APP) and death receptor 6 (DR6) are implicated in neuronal processes.

Purpose of the Study:

• To elucidate the mechanistic basis of axonal pruning and neuronal cell death.
• To investigate the roles of APP and DR6 in a caspase-dependent self-destruction pathway.

Main Methods:

• In vivo and in vitro studies using trophic-factor deprivation.
• Loss- and gain-of-function studies in mutant mice.
• Analysis of caspase activation patterns and APP shedding.

Main Results:

• DR6 is essential for axonal pruning and cell body death in developing neurons.
• Axonal degeneration requires caspase 6, activated in a punctate pattern.
• APP acts as a DR6 ligand, with its N-terminal fragment (N-APP) triggering degeneration upon shedding.
• A neuromuscular junction phenotype was observed in mutant mice.

Conclusions:

• APP and DR6 constitute a neuronal self-destruction pathway.
• An extracellular APP fragment, via DR6 and caspase 6, contributes to neurodegeneration and potentially Alzheimer's disease.