Targeting RPSA to modulate endosomal trafficking and amyloidogenesis in genetic Alzheimer's disease

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Alzheimer's disease (AD) pathogenesis is complex, involving multiple processes beyond the amyloid cascade hypothesis.
• The endocytic pathway is implicated as a pathogenic hub in AD, particularly in the processing of amyloid precursor protein (APP).
• Previous research identified the RPSA receptor and its inhibitor NSC47924 as participants in APP metabolism.

Purpose of the Study:

• To investigate the role of endosomal pathway dysfunction in AD pathogenesis.
• To explore the therapeutic potential of modulating APP processing via the endosomal pathway.
• To examine the effect of RPSA inhibition on APP trafficking and processing in AD fibroblasts.

Main Methods:

• Utilized fibroblasts from patients with a genetic form of AD (APP V717I mutation).
• Analyzed endolysosomal compartment homeostasis and dynamics.
• Assessed APP trafficking, processing, and amyloid-beta (Aβ) production following RPSA inhibition with NSC47924.

Main Results:

• Observed altered endolysosomal homeostasis and APP trafficking in AD fibroblasts.
• Demonstrated that RPSA inhibition reduced APP accumulation in early endosomes (EEs) and restored normal endosomal dynamics.
• Showed that RPSA inhibition decreased the production of APP-βCTF and Aβ in AD fibroblasts.

Conclusions:

• Endosomal pathway dysfunction and altered APP processing are significant in AD-affected cells.
• RPSA inhibition normalizes endosomal dynamics and APP processing, reducing Aβ production.
• Targeting the APP/RPSA interaction presents a promising therapeutic strategy for Alzheimer's disease.