Abstract | November 8, 2021

Intranasal Deferoxamine Modulates Memory, Neuroinflammation, and the Neuronal Transcriptome in the Streptozotocin Rodent Model of Alzheimer Disease

Presenting Author: Jacob Kosyakovsky, B.S, Medical Student, School of Medicine, University of Virginia, Charlottesville, VA, Charlottesville, VA

Coauthors: Jared Fine, Ph.D, Research Associate, HealthPartners Neuroscience Center, St. Paul, MN; Benjamin Stroebel, B.S., Senior Research Assistant, HealthPartners Neuroscience Center, St. Paul, MN; Tate Bowe, B.S., Research Assistant, HealthPartners Neuroscience Center, St. Paul, MN; William H. Frey II, Ph.D, Senior Director, HealthPartners Neuroscience Center, St. Paul, MN; Leah Hanson, Ph.D, Senior Director, HealthPartners Neuroscience Center, St. Paul, MN

Learning Objectives

  1. Describe the advantages and disadvantages of the streptozotocin model of Alzheimer Disease;
  2. Discuss the mechanisms by which deferoxamine may counter Alzheimer pathogenesis;
  3. Identify areas for future research to better understand Alzheimer disease and generate targets for therapeutic intervention.

Background: Intranasal (IN) Deferoxamine (DFO) has emerged over the past decade as a remarkably promising candidate therapeutic in preclinical development across neurodegenerative and neurovascular disease. As an iron chelator, its mechanisms are multimodal, involving the binding of brain iron and the consequent engagement of several disease-nonspecific pathways to counter pathogenesis across multiple diseases. We and other research groups have shown that IN DFO rescues cognitive impairment in several rodent models of Alzheimer Disease (AD), including the inducible intracerebroventricular (ICV) streptozotocin (STZ) rat model. 

Methods: We designed this study in an effort to ease the translation of IN DFO to clinical trials, probing dosing regimes and mechanisms within the ICV STZ model. 

Results: We found that a 1%, but not 0.1%, solution of IN DFO rescued cognitive impairment caused by ICV STZ administration as measured by the Morris Water Maze (MWM) test. Treatment with IN DFO rescued STZ-induced hippocampal neuron loss and decreased hippocampal apoptosis. Furthermore, IN DFO modulated several aspects of the neuroinflammatory milieu of the ICV STZ model, which we assessed through a novel panel of brain cytokines and immunohistochemistry. Using RNA-sequencing and pathway analysis, we found that STZ induced several pathways of cell death and neuroinflammation, and that IN DFO engaged multiple transcriptomic pathways involved in hippocampal neuronal survival. 

Conclusions: In sum, to our knowledge this study represents the first to assess the transcriptomic pathways and mechanisms associated with either the ICV STZ model or DFO treatment, and the first to demonstrate this therapeutic’s efficacy at low doses. We significantly elucidate the mechanisms and role of the ICV-STZ rodent model of AD. We present these mechanisms and methods as a framework for future therapeutic development. 

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