Altered Insulin/Insulin-Like Growth Factor Signaling in a Comorbid Rat model of Ischemia and \u03b2-Amyloid Toxicity

Zareen Amtul,David F Cechetto,Edith J Arany,David J Hill

doi:10.1038/s41598-018-22985-4

Zareen Amtul, David F Cechetto + Show 2 more

Open Access

https://doi.org/10.1038/s41598-018-22985-4

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Abstract

Ischemic stroke and diabetes are vascular risk factors for the development of impaired memory such as dementia and/or Alzheimer’s disease. Clinical studies have demonstrated that minor striatal ischemic lesions in combination with β-amyloid (Aβ) load are critical in generating cognitive deficits. These cognitive deficits are likely to be associated with impaired insulin signaling. In this study, we examined the histological presence of insulin-like growth factor-I (IGF-1) and insulin receptor substrate (IRS-1) in anatomically distinct brain circuits compared with morphological brain damage in a co-morbid rat model of striatal ischemia (ET1) and Aβ toxicity. The results demonstrated a rapid increase in the presence of IGF-1 and IRS-1 immunoreactive cells in Aβ + ET1 rats, mainly in the ipsilateral striatum and distant regions with synaptic links to the striatal lesion. These regions included subcortical white matter, motor cortex, thalamus, dentate gyrus, septohippocampal nucleus, periventricular region and horizontal diagonal band of Broca in the basal forebrain. The alteration in IGF-1 and IRS-1 presence induced by ET1 or Aβ rats alone was not severe enough to affect the entire brain circuit. Understanding the causal or etiologic interaction between insulin and IGF signaling and co-morbidity after ischemia and Aβ toxicity will help design more effective therapeutics.

Highlights

Clinical investigations have clearly established an interaction between Alzheimer’s disease (AD) and ischemia[3]
Studies in patients clearly indicate impaired insulin signaling in both AD and stroke, there has been little investigation of insulin or IGF signaling as a consequence of striatal ischemia and Aβ toxicity, as well as the etiologic link between ischemia and AD
Aβ toxicity showed an effect on IGF-1 and IRS-1 presence, it was significantly altered in various brain regions such as dentate gyrus and septohippocampal nucleus as mentioned below

Summary

Introduction

Clinical investigations have clearly established an interaction between Alzheimer’s disease (AD) and ischemia[3]. In this regard, we have shown using the present co-morbid striatal ischemia and Aβ toxicity rat model, the presence of high levels of endogenous amyloid, amyloid precursor protein (APP), microgliosis, astrocytosis and increased ischemia size in cortical, striatal and hippocampal regions that eventually led to cognitive deficits[4,5,6]. The clinical literature presents a compelling argument for impaired insulin signaling in the vulnerable brains, such as those developing Alzheimer’s type pathologies[7,8] or ischemia.

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