Molecular interplay between leptin, insulin-like growth factor-1, and β-amyloid in organotypic slices from rabbit hippocampus

Gurdeep Marwarha,Jaya Rp Prasanthi,Bhanu Dasari,Othman Ghribi,Jared Schommer

doi:10.1186/1750-1326-6-41

Gurdeep Marwarha, Jaya Rp Prasanthi + Show 3 more

Open Access

https://doi.org/10.1186/1750-1326-6-41

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Journal: Molecular Neurodegeneration	Publication Date: Jun 8, 2011
Citations: 105	License type: cc-by

Affiliation: University of North Dakota

Abstract

BackgroundEvidence shows that the insulin-like growth factor-1 (IGF-1) and leptin reduce β-amyloid (Aβ) production and tau phosphorylation, two major hallmarks of Alzheimer's disease (AD). IGF-1 expression involves the JAK/STAT pathway and the expression of leptin is regulated by the mammalian target of rapamycin complex 1 (mTORC1). We have previously shown that Aβ reduces leptin by inhibiting the mTORC1 pathway and Aβ was also suggested to inhibit the JAK/STAT pathway, potentially attenuating IGF-1 expression. As IGF-1 can activate mTORC1 and leptin can modulate JAK/STAT pathway, we determined the extent to which IGF-1 and leptin can upregulate the expression of one another and protect against Aβ-induced downregulation.ResultsWe demonstrate that incubation of organotypic slices from adult rabbit hippocampus with Aβ42 downregulates IGF-1 expression by inhibiting JAK2/STAT5 pathway. Leptin treatment reverses these Aβ42 effects on IGF-1 and treatment with the STAT5 inhibitor completely abrogated the leptin-induced increase in IGF-1. Furthermore, EMSA and ChIP analyses revealed that leptin increases the STAT5 binding to the IGF-1 promoter. We also show that IGF-1 increases the expression of leptin and reverses the Aβ42-induced attenuation in leptin expression via the activation of mTORC1 signaling as the mTORC1 inhibitor rapamycin completely precluded the IGF-1-induced increase in leptin expression.ConclusionOur results demonstrate for the first time that Aβ42 downregulates IGF-1 expression and that leptin and IGF-1 rescue one another from downregulation by Aβ42. Our study provides a valuable insight into the leptin/IGF-1/Aβ interplay that may be relevant to the pathophysiology of AD.

Highlights

Evidence shows that the insulin-like growth factor-1 (IGF-1) and leptin reduce b-amyloid (Ab) production and tau phosphorylation, two major hallmarks of Alzheimer’s disease (AD)
Our study provides a valuable insight into the leptin/ IGF-1/Ab interplay that may be relevant to the pathophysiology of AD
Ab42 decreases IGF-1 expression levels and treatment with exogenous leptin reverses the effects of Ab42 Western blotting and densitometric analysis (Figure 1a, b) show a decrease in IGF-1 levels in the organotypic hippocampal slices treated with Ab42 compared to untreated organotypic slices

Summary

Introduction

Evidence shows that the insulin-like growth factor-1 (IGF-1) and leptin reduce b-amyloid (Ab) production and tau phosphorylation, two major hallmarks of Alzheimer’s disease (AD). IGF-1 expression involves the JAK/STAT pathway and the expression of leptin is regulated by the mammalian target of rapamycin complex 1 (mTORC1). We have previously shown that Ab reduces leptin by inhibiting the mTORC1 pathway and Ab was suggested to inhibit the JAK/STAT pathway, potentially attenuating IGF-1 expression. There is compelling evidence that the insulin-like growth factor-1 (IGF-1) is involved in the metabolism and clearance of Ab [1,2]. IGF-1 expression is contingent on the activation of the JAK/STAT pathway, involving the transcription factor STAT5 [10,11]

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