Identification of Human Islet Amyloid Polypeptide as a BACE2 Substrate

Area of Science:

• Biochemistry
• Cell Biology
• Endocrinology

Background:

• Islet amyloid polypeptide (IAPP) amyloid formation is a key pathological feature in type 2 diabetes.
• IAPP is stored and co-secreted with insulin by pancreatic beta-cells for glucose homeostasis.
• Dysregulation of IAPP production or processing leads to cytotoxic oligomers, amyloid fibrils, beta-cell dysfunction, and plaque accumulation.

Purpose of the Study:

• To investigate the proteolytic activity of Beta-site APP-cleaving enzyme 2 (BACE2) on human IAPP.
• To determine if BACE2 can modulate IAPP fibrillation and protein degradation.
• To explore the potential therapeutic role of BACE2 in type 2 diabetes-associated hyperamylinaemia.

Main Methods:

• Enzymatic assays to identify BACE2 cleavage sites on mature human IAPP.
• Analysis of BACE2's effect on IAPP fibrillation kinetics.
• Assessment of BACE2's impact on IAPP protein degradation pathways.

Main Results:

• Identified two specific sites on human IAPP susceptible to BACE2-mediated proteolysis.
• Demonstrated that BACE2 activity modulates the fibrillation of human IAPP.
• Showed that BACE2 promotes the degradation of human IAPP protein.

Conclusions:

• BACE2 exhibits proteolytic activity against human IAPP at distinct sites.
• BACE2-mediated proteolysis influences IAPP aggregation and stability.
• BACE2 represents a potential therapeutic target for managing type 2 diabetes by addressing hyperamylinaemia.