HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Mechanisms of Neurodegeneration

Background:

• Amyloid precursor protein (APP) is crucial for neuronal function but generates toxic Aβ in Alzheimer's disease (AD).
• Endo-lysosomal system regulates APP processing, yet underlying mechanisms remain unclear.
• The HOPS complex is a key regulator of endo-lysosomal maturation.

Purpose of the Study:

• To investigate the role of the HOPS complex in APP trafficking and processing.
• To elucidate the molecular mechanisms linking HOPS function to neurodegeneration in AD.

Main Methods:

• Studied the HOPS complex's role in endo-lysosomal maturation and APP processing.
• Analyzed APP trafficking, localization, and processing in the context of HOPS disruption.
• Investigated the presence of APP C-terminal fragments (APP-CTFs) and secretase activity in affected endosomes.

Main Results:

• HOPS disruption impairs retromer-mediated APP recycling to the Trans-Golgi Network (TGN).
• APP accumulates in somatodendritic late endosomes, which lack PSEN2 but contain BACE1, promoting APP-CTF accumulation.
• Loss of HOPS function increases exosomal secretion of APP-CTFs, suggesting a disease propagation mechanism.

Conclusions:

• HOPS complex loss-of-function mechanistically links aberrant APP processing to neurodegeneration.
• Impaired APP recycling and increased APP-CTF secretion are consequences of HOPS dysfunction.
• Findings offer insights into AD pathogenesis and potential therapeutic targets.