Abstract
Background
There is high incidence of cerebral amyloid beta (Aβ) deposition in insulin-resistant type 2 diabetes mellitus. Low-density lipoprotein receptor-related protein 1 (LRP-1) mediates the 40-amino-acid form of Aβ (Aβ1-40) efflux from brain to periphery. In LRP-1-mediated Aβ regulation, insulin and peroxisome proliferator-activated receptor-γ (PPARγ) were found to have important effect on the expression and function of LRP-1. We therefore hypothesised that insulin and PPARγ-agonist (rosiglitazone), alone or in combination may affect LRP-1 distribution and expression, and then reduce Aβ1-40 deposition in diabetes brain.
Methods
Goto-Kakizaki (GK) rats were used as type 2 diabetic rats model. The expression of LRP-1 and Aβ1-40 in brain microvessels was detected by immunohistochemistry. The expression levels of LRP-1 and Aβ1-40 in brain tissue were estimated by enzyme-linked immunosorbent assays (ELISA). LRP-1mRNA was detected by RT-PCR.
Results
With diabetes mellitus progression, Aβ1-40 deposition in brain tissue increased obviously. Administration of rosiglitazone to GK rats caused significant increase in the LRP-1 protein content and specific mRNA level of this receptor with reduction of levels of Aβ1-40 in GK brain tissue when compared to GK group. Also, there was a significant increase in the LRP-1 protein content in plasma membrane fraction of brain tissue, whereas the expression in the whole lysate was not affected with a significant reduction of levels of Aβ1-40 in GK brain by insulin treatment. Compared to GK with insulin group, there was a great increase in the LRP-1 protein content in the brain in the group administered a combination of insulin with rosiglitazone.
Conclusions
Insulin or rosiglitazone could decrease accumulation of Aβ1-40 in the GK brain which appeared to be mediate, at least in part, via LRP-1 and in combination use, rosiglitazone seemed to be able to sensitize/enhance insulin's inducing the subcellular translocation of LRP-1 to the plasma membrane. In this context, it is probably beneficial to combine insulin with rosiglitazone to benefit type 2 diabetes mellitus based on the known LRP1-mediated anti-Aβ1-40 effect.
