Effect of pioglitazone on altered expression of Aβ metabolism-associated molecules in the brain of fructose-drinking rats, a rodent model of insulin resistance

Accumulation of β-amyloid (Aβ) peptide in the brain is a major hallmark of Alzheimer's disease. An optimal brain insulin level promotes Aβ clearance, which may play protective roles against Alzheimer's disease. In this study we examined the role of dietary conditions leading to insulin resistance on amyloidosis in fructose-drinking rats. Further investigations tested pioglitazone, an insulin sensitizer, intervention on the altered amyloidosis in this rodent model of insulin resistance. Six-week-old male Wistar rats were fed a standard commercial diet and water without (control) or with 10% fructose for 16 weeks. The animals were randomly divided into 4 groups (n = 10): non-treated and water-drinking rats (control group); pioglitazone treated and water-drinking (control treatment group); non-treated and fructose-drinking rats (fructose group) and pioglitazone-treated and fructose-drinking rats (fructose treatment group). Pioglitazone was given at the dose of 10 mg/kg d by gavage for the last 12 weeks of the 16-week period. We found that diet-induced insulin resistance induced Aβ overproduction with altered expression of Aβ metabolism-associated molecules, which corresponded with increased β-secretase-1 (BACE1), γ-secretase (PS-1) activities and decreased insulin degrading enzyme (IDE) activities, but not neprilysin in the cortex and hippocampus. Additionally, pioglitazone treatment prevented all these observed abnormalities. This study indicates that insulin resistance induced by fructose-drinking affects the expression of Aβ metabolism-associated molecules that are responsible for Aβ deposition and pioglitazone treatment negatively modulate amyloidogenesis.