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A New Approach to Model Sporadic Alzheimer’s Disease by Intracerebroventricular Streptozotocin Injection in APP/PS1 Mice

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Abstract

Alzheimer’s disease (AD) is the most common cause of dementia among elderly people. Majority of AD cases are sporadic (SAD) with unknown cause. Transgenic animal models closely reflect the familial (genetic) aspect of the disease but not the sporadic type. However, most new drug candidates which are tested positive in transgenic animal models failed in clinical studies so far. Herein, we aim to develop an AD animal model that combines most of the neuropathological features seen in sporadic AD in humans with amyloid plaques observed in transgenic mice. Four-month-old wild-type and APP/PS1 AD mice were given a single intracerebroventricular (ICV) injection of 3 mg/kg streptozotocin (STZ), a diabetogenic agent. Three weeks later, their cognitive behavior was assessed, and their brain tissues were collected for biochemical and histological analysis. STZ produced cognitive deficits in both non-transgenic mice and AD mice. Biochemical analysis showed a severe decline in synaptic proteins, increase in tau phosphorylation, oxidative stress, disturbed brain insulin signaling with extensive neuroinflammation, and cell death. Significant increase was also observed in the level of the soluble beta amyloid precursor protein (APP) fragments and robust accumulation of amyloid plaques in AD mice compared to the control. These results suggest that STZ ICV treatment causes disturbance in multiple metabolic and cell signaling pathways in the brain that facilitated amyloid plaque accumulation and tau phosphorylation. Therefore, this animal model can be used to evaluate new AD therapeutic agents for clinical translation.

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Acknowledgements

The authors acknowledge the support provided to S. Kelliny by Commonwealth Research and Training scholarship and Egyptian Ministry of Higher Education. We would like to thank Dr Lewis Vaughan for technical assistance regarding the surgical procedure and Mr. Andrew Beck for suggestions regarding histological techniques and imaging.

Funding

This study was supported by the National Health and Medical Research Council (NHMRC) grants (1020567, 1021409) and supporting grant from the University of South Australia.

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Authors and Affiliations

  1. Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia

    Sally Kelliny, Liying Lin, Isaac Deng, Jing Xiong, Fiona Zhou, Mohammed Al-Hawwas, Larisa Bobrovskaya & Xin-Fu Zhou

  2. Faculty of Pharmacy, Assiut University, Assiut, Egypt

    Sally Kelliny

  3. Department of Neurology, The Second Affiliated Hospital, Kunming Medical University, Kunming, Yunnan Province, China

    Jing Xiong

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  1. Sally Kelliny
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  2. Liying Lin
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  3. Isaac Deng
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  6. Mohammed Al-Hawwas
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  7. Larisa Bobrovskaya
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  8. Xin-Fu Zhou
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Contributions

Larisa Bobrovskaya and Xin-Fu Zhou contributed to the study conception and design. Material preparation, experiments, data collection, and analysis were performed by Sally Kelliny. Liying Lin participated in tissue staining experiments; Isaac Deng, Jing Xiong, Fiona Zhou, and Mohammed Al-Hawwas collaborated in animal studies. The first draft of the manuscript was written by Sally Kelliny and all authors commented on previous versions of the manuscript. Larisa Bobrovskaya and Xin-Fu Zhou supervised the study. All the authors reviewed and approved the final version of the manuscript submitted.

Corresponding authors

Correspondence to Larisa Bobrovskaya or Xin-Fu Zhou.

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Ethics Approval

All procedures were compliant with the approved protocol (U26-15) from the Animal Ethics Committee of the University of South Australia and the South Australia animal welfare act and the “Australian code of practice and use of animals for scientific purposes.”

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Kelliny, S., Lin, L., Deng, I. et al. A New Approach to Model Sporadic Alzheimer’s Disease by Intracerebroventricular Streptozotocin Injection in APP/PS1 Mice. Mol Neurobiol 58, 3692–3711 (2021). https://doi.org/10.1007/s12035-021-02338-5

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