Effect of rosiglitazone on amyloid precursor protein processing and Aβ clearance in streptozotocin-induced rat model of Alzheimer’s disease

Objective(s): Increasing evidence suggests that Alzheimer’s disease (AD) is associated with diabetes. Rosiglitazone, a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist and anti-diabetic agent, may improve symptoms of AD. However, the underlying therapeutic potential of it has not been fully elucidated. Materials and Methods: Rats were divided into four groups: control group, sham operated group, Streptozotocin (STZ) group, rosiglitazone (RGZ) group. Particularly, the STZ-induced rat model was established by intracerebroventricular injection (۳ mg/kg) on the first and third day. The water maze behavioral test was performed to evaluate spatial reference learning and memory of the rats. Aβ۱-۴۰ and Aβ۱-۴۲ levels were measured by ELISA method. To determine APP-derived fragment, BACE۱ and Aβ degrading enzymes levels, such as NEP and IDE, as well as Aβ transportation protein level, such as LRP۱, RAGE, Abca۱ and APOE , which were analyzed by Western blot. Immunohistochemistry was used to observe the change of Aβ۱-۴۰ and Aβ۱-۴۲ in hippocampus. Results: Chronic treatment with RGZ could reduce the Aβ level and improved spatial memory performance in STZ-induced rat model. However, RGZ modified the expression of specific transport proteins monitoring Aβ clearance, such as ATP-binding cassette transporter ۱ (ABCA۱), lipoprotein receptor-related protein ۱ (LRP۱), and the advanced glycation end product-specific receptor (RAGE) rather than change levels of Aβ degrading enzymes, such as IDE and NEP, nor affect APP processing.  Conclusion: As a potential therapeutic strategy, rosiglitazone might exert anti-AD effect not by alteration of APP processing pathway and Aβ degradation directly, but through promotion of Aβ clearance indeed.

Keywords:

Alzheimer’s disease , Amyloid precursor protein processing , β-amyloid peptide clearance , Peroxisome proliferator activated receptor γ