A尾1-40 clearance from the brain by regulation of LRP-1: A study on effects of insulin, rosiglitazone or the combination in type 2 diabetic GK rats

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• 作者：Meijia Zhu^a ; ¹ ; ^{dr_zhumeijia@126.com} ; Wenjuan Xu^b ; ¹ ; Zhangning Zhao^a ; Gaoting Ma^a ; Mengxin Bao^b ; Zhongwen Sun^b
• 关键词：LRP-1 ; A尾1-40 ; Insulin ; PPAR纬-agonist ; GK ; Diabetes
• 刊名：Biomedicine & Aging Pathology
• 出版年：2012
• 期刊代码：pca72_22105220
• 类别：med
• 出版时间：April-June, 2012
• 卷：2
• 期：2
• 页码：54-60
• 文件大小：926 K

摘要

Background

There is high incidence of cerebral amyloid beta (A尾) deposition in insulin-resistant type 2 diabetes mellitus. Low-density lipoprotein receptor-related protein 1 (LRP-1) mediates the 40-amino-acid form of A尾 (A尾1-40) efflux from brain to periphery. In LRP-1-mediated A尾 regulation, insulin and peroxisome proliferator-activated receptor-纬 (PPAR纬) were found to have important effect on the expression and function of LRP-1. We therefore hypothesised that insulin and PPAR纬-agonist (rosiglitazone), alone or in combination may affect LRP-1 distribution and expression, and then reduce A尾1-40 deposition in diabetes brain.

Methods

Goto-Kakizaki (GK) rats were used as type 2 diabetic rats model. The expression of LRP-1 and A尾1-40 in brain microvessels was detected by immunohistochemistry. The expression levels of LRP-1 and A尾1-40 in brain tissue were estimated by enzyme-linked immunosorbent assays (ELISA). LRP-1mRNA was detected by RT-PCR.

Results

With diabetes mellitus progression, A尾1-40 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 A尾1-40 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 A尾1-40 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 A尾1-40 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-A尾1-40 effect.