Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer's Disease: in Search of a Relevant Mechanism.

Paweł Grieb

doi:10.1007/s12035-015-9132-3

Paweł Grieb

Open Access

https://doi.org/10.1007/s12035-015-9132-3

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Abstract

Streptozotocin (STZ), a glucosamine-nitrosourea compound derived from soil bacteria and originally developed as an anticancer agent, in 1963 has been found to induce diabetes in experimental animals. Since then, systemic application of STZ became the most frequently studied experimental model of insulin-dependent (type 1) diabetes. The compound is selectively toxic toward insulin-producing pancreatic beta cells, which is explained as the result of its cellular uptake by the low-affinity glucose transporter 2 (GLUT2) protein located in their cell membranes. STZ cytotoxicity is mainly due to DNA alkylation which results in cellular necrosis. Besides pancreatic beta cells, STZ applied systemically damages also other organs expressing GLUT2, such as kidney and liver, whereas brain is not affected directly because blood-brain barrier lacks this transporter protein. However, single or double intracerebroventricular (icv) STZ injection(s) chronically decrease cerebral glucose uptake and produce multiple other effects that resemble molecular, pathological, and behavioral features of Alzheimer’s disease (AD). Taking into consideration that glucose hypometabolism is an early and persistent sign of AD and that Alzheimer’s brains present features of impaired insulin signaling, icv STZ injections are exploited by some investigators as a non-transgenic model of this disease and used for preclinical testing of pharmacological therapies for AD. While it has been assumed that icv STZ produces cerebral glucose hypometabolism and other effects directly through desensitizing brain insulin receptors, the evidence for such mechanism is poor. On the other hand, early data on insulin immunoreactivity showed intense insulin expression in the rodent brain, and the possibility of local production of insulin in the mammalian brain has never been conclusively excluded. Also, there are GLUT2-expressing cells in the brain, in particular in the circumventricular organs and hypothalamus; some of these cells may be involved in glucose sensing. Thus, icv STZ may damage brain glucose insulin producing cells and/or brain glucose sensors. Mechanistic explanation of the mode of action of icv STZ, which is currently lacking, would provide a valuable contribution to the field of animal models of Alzheimer’s disease.

Highlights

Laboratory animals, mostly rodents, are commonly used as models of human diseases. The concept of such models is based on a certain degree of Banalogy^ between pathological processes that occur during progression of a disease in patients and in animals being studied as their substitute [1]
In the brains of adult icv STZ-treated rats, Deng et al [75] found impaired insulin signaling, overactivation of glycogen synthase kinase-3β, decreased levels of major brain glucose transporters, downregulated protein O-GlcNAcylation, as well as increased phosphorylation of tau and neurofilaments and decreased microtubule-binding activity of tau. These authors suggested that the key mechanism in the development of disease in the human Alzheimer’s disease (AD), as well as in the rodent model disease is the development of brain insulin resistance which leads to neurofibrillary degeneration via two cooperating pathways, namely decreased PI3K-AKT signaling activity and glycogen synthase kinase 3 beta (GSK3β) overactivation and decreased GLUT1/3 expression and decreased intraneuronal glucose metabolism
Chen et al [76] observed that icv STZ injection exacerbates memory disturbances and Alzheimer-like neurochemical changes in brains of 3xTg-AD mice, concluding that these findings demonstrate the role of metabolic insult in AD pathology in vivo

Summary

Introduction

Laboratory animals, mostly rodents, are commonly used as models of human diseases. The concept of such models is based on a certain degree of Banalogy^ between pathological processes that occur during progression of a disease in patients and in animals being studied as their substitute [1]. The aim of the present paper is to compare the assumptions underlying the icv STZ model and the transgenic models of AD and to discuss mechanism(s) which may be involved in the development of Alzheimer’s-like neuropathology in rodents following single or double injection of streptozotocin into the lateral ventricles.

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