APP intracellular domain is increased and soluble Aβ is reduced with diet-induced hypercholesterolemia in a transgenic mouse model of Alzheimer disease

Abstract

Cholesterol is one of multiple factors, other than familial genetic mutations, that can influence amyloid-β peptide (Aβ) metabolism and accumulation in Alzheimer disease (AD). The effect of a high-cholesterol diet on amyloid precursor protein (APP) processing in brain has not been thoroughly studied. This study was designed to further investigate the role of cholesterol in the production of Aβ and APP intracellular domain (AICD) in 12-month-old Tg2576 transgenic mice. The mice were maintained on a high-cholesterol diet for 6 weeks. We found that diet-induced hypercholesterolemia increased the APP cytosolic fragment AICD and reduced sAPPα in the Tg2576 mice compared to the mice on a control basal diet. In addition, the levels of detergent-extracted Aβ40 were reduced, although no change in guanidine-extracted Aβ levels was observed. Full-length APP, α/βC-terminal fragment (α/βCTF), and β-secretase (BACE) were not different in the cholesterol-fed mice compared to the control diet-fed mice. This study suggests that a high dietary cholesterol in aged mice may not only influence Aβ metabolism, but also regulate the AICD levels. AICD has a proposed role in signal transduction and apoptosis, hence modulation of AICD production could be an alternative mechanism by which cholesterol contributes to AD pathogenesis.

Keywords

• Alzheimer disease
• Transgenic mouse
• Aβ amyloid
• Amyloid precursor protein
• AICD
• Cholesterol