The US9-Derived Protein gPTB9TM Modulates APP Processing Without Targeting Secretase Activities

Area of Science:

• Neuroscience
• Molecular Biology
• Virology

Background:

• Neuronal protein processing, particularly amyloid precursor protein (APP) amyloidogenic processing in vesicles, is critical in neurological disorders.
• Current strategies focus on inhibiting enzymes like β-secretase, but alternative approaches are needed.

Purpose of the Study:

• To develop a novel strategy for redirecting APP processing to favor non-amyloidogenic pathways.
• To investigate the use of herpes simplex virus 1 (HSV-1) transport protein US9 for guiding APP trafficking.

Main Methods:

• Engineered a US9 chimeric construct to influence APP processing.
• Tested the construct in primary cortical neurons to assess its effects on APP processing and neuronal health.

Main Results:

• Reduced amyloid β production and APP/tau phosphorylation.
• Promoted the release of neuroprotective soluble αAPP.
• Leveraged endogenous neuronal proteins for US9-driven effects.

Conclusions:

• The US9-based method offers a new way to limit APP misprocessing and its consequences.
• This approach provides a novel tool for reducing cognitive decline in conditions like Alzheimer's disease and HIV-associated neurocognitive disorders.