Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction

Area of Science:

• Biomedical research
• Cardiovascular science
• Neurodegenerative disease research

Background:

• Diabetes, obesity, and Alzheimer's disease (AD) are linked to vascular issues and reduced nitric oxide (NO) production.
• Elevated β-site APP-cleaving enzyme 1 (BACE1), APP, and β-amyloid (Aβ) are associated with vascular disease, hyperglycemia, and hyperlipidemia.

Purpose of the Study:

• To investigate the causal link between obesity, diabetes, increased Aβ, and vascular dysfunction.
• To explore the therapeutic potential of targeting BACE1 and Aβ42 in vascular complications.

Main Methods:

• Diet-induced obesity (DIO) in mice was used to study plasma and vascular Aβ42 levels, NO bioavailability, endothelial function, and blood pressure.
• Genetic or pharmacological inhibition of BACE1 and Aβ42 was employed.
• Experiments involved expressing human mutant APP or infusing Aβ42 into control mice.
• Human plasma Aβ42 levels were correlated with diabetes and endothelial dysfunction.

Main Results:

• DIO mice exhibited increased plasma and vascular Aβ42, decreased NO bioavailability, endothelial dysfunction, and elevated blood pressure.
• BACE1/Aβ42 reduction prevented and reversed these effects.
• Human mutant APP expression or Aβ42 infusion impaired NO production, vascular relaxation, and increased blood pressure.
• In humans, higher plasma Aβ42 correlated with diabetes and endothelial dysfunction.
• Mechanistically, elevated Aβ42 reduced eNOS/cGMP/PKG activity and increased endothelin-1, effects reversed by lowering Aβ42.

Conclusions:

• Increased Aβ42 plays a causal role in obesity- and diabetes-associated vascular dysfunction.
• Targeting BACE1 to reduce Aβ42 shows promise for treating vascular complications in diabetes.