Top

Published in:

01-04-2015 | Original Article

The β-amyloid precursor protein analog P165 improves impaired insulin signal transduction in type 2 diabetic rats

Authors: Lina Ma, Zhimin Shao, Rong Wang, Zhiwei Zhao, Xu Zhang, Zhijuan Ji, Shuli Sheng, Baolei Xu, Wen Dong, Jingshuang Zhang

Published in: Neurological Sciences | Issue 4/2015

Abstract

This study was performed to understand whether P165 improves learning and memory by restoring insulin action using a diabetes mellitus (DM) rat model. A total of 34 male Sprague–Dawley rats were randomly divided into four groups: control group (n = 8), DM group (n = 8), DM group treated with a low dose of P165 (n = 9), and DM group treated with a high dose of P165 (n = 9). After 8 weeks of treatment, the animals were killed and the expression of insulin signaling-related proteins was examined in the hippocampus by Western blot and immunohistochemical staining. Administration of P165 in diabetic rats did not induce a significant effect on the fasting blood glucose level. The expression of IR, IRS-1, AKT, p-CREB, and Bcl-2 proteins was significantly enhanced in the hippocampus in diabetic rats. Treatment of diabetic rats with P165 at both low and high doses significantly attenuated the expression levels of these proteins. Moreover, immunohistochemistry staining showed that IR, IRS-1, AKT, p-CREB, and Bcl-2 were abundantly expressed in the CA1 region of the hippocampus. The number of cells positively stained for the above proteins was significantly higher in diabetic tissues compared to control tissues, whereas P165 treatments induced a significant reduction in the expression of these proteins. The expression of IR, IRS-1, AKT, p-CREB, and Bcl-2 was enhanced in DM rats, and administration of P165 normalized the expression of these molecules, suggesting that P165 can improve impaired insulin signal transduction.

Wei B, Frank BH, Shuang R et al (2013) Predicting risk of type 2 diabetes mellitus with genetic risk models on the basis of established genome-wide association markers: a systematic review. Am J Epidemiol 178:1197–1207CrossRef

Namba M, Katsuno T, Kusunoki Y et al (2013) New strategy for the treatment of type 2 diabetes mellitus with incretin-based therapy. Clin Exp Nephrol 17:10–15CrossRefPubMed

Callisaya M, Moran C (2013) Type 2 Diabetes mellitus as a causal factor for dementia-is there sufficient evidence from interventional studies? Australas epidemiol 20:26–28

Sung MS, Hyundong S, Jayoung B et al (2012) Altered APP processing in insulin-resistant conditions is mediated by autophagosome accumulation via the inhibition of mammalian target of rapamycin pathway. Diabetes 61:3126–3138CrossRef

Profenno LA, Porsteinsson AP, Faraone SV (2010) Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 67:505–512CrossRefPubMed

Triggle CR, Howarth A, Cheng ZJ et al (2005) Twenty-five years since the discovery of endothelium-derived relaxing factor (EDRF): does a dysfunctional endothelium contribute to the development of type 2 diabetes? Can J Physiol Pharmacol 83:681–700CrossRefPubMed

Vogt MC, Brüning JC (2013) CNS insulin signaling in the control of energy homeostasis and glucose metabolism-from embryo to old age. Trends Endocrinol Metab 24:76–84CrossRefPubMed

Liu L, Yan T, Jiang L et al (2013) Pioglitazone ameliorates memory deficits in streptozotocin-induced diabetic mice by reducing brain β-amyloid through PPARγ activation. Acta Pharmacol 34:455–463CrossRef

Zhao YM, Pei JJ, Ji ZJ et al (2003) Effect of amyloid precursor protein 17-mer peptide on microtubule structure and tau protein hyperphosphorylation in hippocampal neurons of experimental diabetic mice. Neuro Report 14:61–66

10.

Meng Y, Wang R, Yang F et al (2010) Amyloid precursor protein 17-mer peptide ameliorates hippocampal neurodegeneration in ovariectomized rats. Neurosci Lett 468:173–177CrossRefPubMed

11.

Yao J, Wang R, Ji Z et al (2007) The in vitro experimental research on neurotrophic effect of the analogs of APP 5-mer peptide. Chin J Mult Organ Dis Elder 6:52–56

12.

Duron E, Olivier H (2008) Vascular risk factors, cognitive decline, and dementia. Vasc Health Risk Manag 4:363–381PubMedCentralPubMed

13.

Han X, Ma Y, Liu X et al (2012) Changes in insulin-signaling transduction pathway underlie learning/memory deficits in an Alzheimer’s disease rat model. J Neural Transm 119:1407–1416CrossRefPubMed

14.

Biessels GJ, van der Heide LP, Kamal A et al (2002) Ageing and diabetes: implications for brain function. Eur J Pharmacol 441:1–14CrossRefPubMed

15.

Son SM, Jung ES, Shin HJ et al (2012) Aβ-induced formation of autophagosomes is mediated by RAGE-CaMKKβ-AMPK signaling. Neurobiol Aging 33:11–23CrossRef

16.

Shen C, Chen Y, Liu H et al (2008) Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase. J Biol Chem 283:17721–17730PubMedCentralCrossRefPubMed

17.

Yamamoto KT, Miyoshi T, Yea K et al (1994) The survival of rat cerebral cortical neurons in the presence of trophic APP peptide. J Neurobiol 25:585–594CrossRefPubMed

18.

Roch JM, Masliah E, Roch-Levecq AC et al (1994) Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. Proc Natl Acad Sci USA 91:7450–7454PubMedCentralCrossRefPubMed

19.

Zhang J, Meng Y, Wang R et al (2008) Effect of Wortmannin and APP 17-mer peptide on insulin signal transduction pathway of SY5Y cells. Chin J Diabetes 16:429–431

Title: The β-amyloid precursor protein analog P165 improves impaired insulin signal transduction in type 2 diabetic rats
Authors: Lina Ma
Zhimin Shao
Rong Wang
Zhiwei Zhao
Xu Zhang
Zhijuan Ji
Shuli Sheng
Baolei Xu
Wen Dong
Jingshuang Zhang
Publication date: 01-04-2015
Publisher: Springer Milan
Published in: Neurological Sciences / Issue 4/2015
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI: https://doi.org/10.1007/s10072-014-1997-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The β-amyloid precursor protein analog P165 improves impaired insulin signal transduction in type 2 diabetic rats

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2015

Spinal myoclonus in a patient with hepatic encephalopathy

Parkinson’s disease associated with myasthenia gravis and rheumatoid arthritis

Bilateral subthalamic stimulation for advanced Parkinson disease: early experience at an Eastern center

Pitfall in neurology: giant cell arteritis mimicking ocular myasthenia gravis

Neuroprotection following acute ischemic stroke: efficacy of preconditioning and antioxidants

RETRACTED ARTICLE: Association of Catechol-O-methyltransferase val/met polymorphism with cognitive function in Gilles de la Tourette syndrome patients