Gene Transfer Induced Hypercholesterolemia in Amyloid Mice

Area of Science:

• Neuroscience
• Cardiovascular Science
• Genetics

Background:

• Cardiovascular disease (CVD) shares risk factors with Alzheimer's disease (AD).
• Elevated cholesterol is a risk factor for CVD.
• The role of hypercholesterolemia in early Alzheimer's disease pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the inter-relationship between cardiovascular disease and Alzheimer's disease.
• To determine if hypercholesterolemia accelerates amyloid-β plaque deposition in a mouse model of Alzheimer's disease.

Main Methods:

• APP/PS1 transgenic mice were used to model Alzheimer's disease.
• Mutant proprotein convertase subtilisin/kexin type 9 (PCSK9) was introduced via gene transfer to induce hypercholesterolemia.
• Cholesterol levels and amyloid-β plaque burden were measured over time.

Main Results:

• PCSK9 gene transfer significantly elevated cholesterol levels (5-6 fold) in mice.
• A modest increase in amyloid-β plaque burden was observed in the hippocampus of PCSK9-treated mice.
• This suggests hypercholesterolemia may influence early stages of plaque deposition.

Conclusions:

• Elevating cholesterol via PCSK9 gene transfer in APP/PS1 mice provides a valuable model for studying the interplay between hypercholesterolemia and Alzheimer's disease.
• This approach offers an alternative to traditional breeding methods for creating combined disease models.