c-Abl links APP-BACE1 interaction promoting APP amyloidogenic processing in Niemann-Pick type C disease

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Niemann-Pick type C (NPC) disease involves lysosomal cholesterol accumulation and increased amyloid-beta (Aβ) peptide levels, linked to Alzheimer's disease (AD).
• The c-Abl tyrosine kinase is active in NPC neurons and AD models, and its inhibitor, Imatinib, reduced brain amyloid burden in an AD mouse model.
• Previous work showed c-Abl interacts with the APP cytosolic domain, but its role in APP processing was unclear.

Purpose of the Study:

• To investigate the role of c-Abl in amyloid precursor protein (APP) processing in NPC disease.
• To determine if c-Abl inhibition affects the amyloidogenic pathway of APP.

Main Methods:

• Treatment of NPC cells overexpressing APP with Imatinib or c-Abl shRNA.
• Analysis of Aβ oligomers and βCTF levels.
• Assessment of APP processing in NPC mouse models and c-Abl null mouse neuronal cultures.
• Investigation of the interaction between c-Abl, APP, and BACE1.

Main Results:

• c-Abl inhibition reduced APP amyloidogenic cleavage, decreasing Aβ oligomers and βCTF levels in NPC cells.
• Imatinib treatment decreased APP amyloidogenic processing in the brain of an NPC mouse model.
• c-Abl directly interacts with APP at Tyr682, and its inhibition prevents this interaction and the APP-BACE1 interaction.

Conclusions:

• c-Abl activity promotes APP amyloidogenic processing by facilitating the APP-BACE1 interaction.
• Inhibiting c-Abl represents a potential pharmacological strategy to mitigate increased Aβ levels in NPC disease.