Modulation of BAG3 Expression and Proteasomal Activity by sAPPα Does Not Require Membrane-Tethered Holo-APP

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Neuronal proteostasis is crucial for brain health and function.
• Disturbed proteostasis is implicated in brain aging and neurodegenerative diseases like Alzheimer's disease (AD).
• Secreted amyloid precursor protein alpha (sAPPα), an APP cleavage product, is known for neuroprotection.

Purpose of the Study:

• To investigate the direct effects of sAPPα on neuronal proteostasis under proteasomal stress.
• To determine if membrane-bound holo-APP is required for sAPPα's effects on proteostasis.
• To assess the selectivity of sAPPα's function compared to sAPPβ.

Main Methods:

• Recombinant sAPPα and sAPPβ were applied to SH-SY5Y neuroblastoma cells and primary hippocampal neurons.
• Cells were subjected to proteasomal stress using MG132.
• Expression of BAG3, aggresome formation, and proteasomal activity were assessed.
• Experiments were conducted in both APP-proficient and APP-deficient cells/neurons.

Main Results:

• Recombinant sAPPα suppressed MG132-induced BAG3 expression and aggresome formation in neuronal cells.
• sAPPα partially rescued proteasomal activity in a dose-dependent manner.
• These effects were observed independently of holo-APP levels.
• Recombinant sAPPβ did not affect BAG3 expression or proteostasis.

Conclusions:

• sAPPα directly modulates neuronal proteostasis, independent of holo-APP.
• The observed effects on proteostasis are specific to sAPPα.
• These findings reveal a novel function of sAPPα and its role in brain aging and APP processing.