New tricks from an old dog: Another synaptotoxic fragment from APP

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• The amyloid precursor protein (APP) is a key protein implicated in neurodegenerative diseases.
• APP processing by secretases is crucial for its function and implicated in disease pathogenesis.

Purpose of the Study:

• To identify novel proteolytic pathways of APP.
• To characterize the functional consequences of newly identified APP fragments.

Main Methods:

• Proteolytic activity assays.
• Mass spectrometry-based proteomics.
• Cellular assays for synaptic function.

Main Results:

• A previously unrecognized cleavage of APP by η-secretase was discovered.
• This cleavage, followed by α- or β-secretase activity, releases a novel APP fragment designated Aη.
• The novel Aη fragment was found to induce synaptic injury in cellular models.

Conclusions:

• The η-secretase pathway represents a novel route for APP processing.
• The Aη fragment is a newly identified pathogenic species that contributes to synaptic dysfunction.
• Targeting this novel pathway may offer new therapeutic strategies for neurodegenerative conditions.