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

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.

Keywords: Brain; Insulin producing cells; Insulin receptors; Intracerebroventricular streptozotocin injection; Non-transgenic Alzheimer’s disease model.

Fig. 1

Diagram presenting chain of causation assumed by the “amyloid cascade” hypothesis

Fig. 2

Diagram listing factors contributing to Aβ oligomerization and its downstream effects. Reproduced from ref. 11 (open access)

Fig. 3

Diagram presenting chain of causation assumed by the “cerebral glucodeprivation” hypothesis

Fig. 4

Structural formula of streptozotocin (STZ)

Fig. 5

Effects of icv STZ (bilaterally, 3 mg/kg body weight, on days 1 and 3) on concentrations of brain metabolites obtained from ¹H-MRS spectra recorded from 27 μL volume comprising hippocampus and part of the cerebral cortex, in 7 T magnetic field strength with very short echo time. a 2 weeks after and b 2 months after icv STZ injection. Mac macromolecules, Asc ascorbate, Asp aspartate, Cr creatine, PCr phosphocreatine, Glc glucose, Gln glutamine, Glu glutamate, Ins inositol, Lac lactate, NAA N-acetylaspartate, NAAG N-acetylaspartylglutamate, PE phosphorylethanolamine, Tau taurine; GPC+PC glycerophosphocholine and phosphocholine, n = 8, error bars show standard deviations, asterisks indicate p < 0.05 by two-tailed t test for independent means. (Reproduced from ref. 68, with permission from Springer-Verlag)