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A Non-transgenic Mouse Model (icv-STZ Mouse) of Alzheimer’s Disease: Similarities to and Differences from the Transgenic Model (3xTg-AD Mouse)

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Abstract

Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and result from multiple etiologic factors, including environmental, genetic, and metabolic factors, whereas FAD is caused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP) genes. A commonly used animal model for AD is the 3xTg-AD transgenic mouse model, which harbors mutated presenilin 1, APP, and tau genes and thus represents a model of FAD. There is an unmet need in the field to characterize animal models representing different AD mechanisms, so that potential drugs for SAD can be evaluated preclinically in these animal models. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study, we compared the non-cognitive and cognitive behaviors as well as biochemical and immunohistochemical alterations between the icv-STZ mouse and the 3xTg-AD mouse. We found that both mouse models showed increased exploratory activity as well as impaired learning and spatial memory. Both models also demonstrated neuroinflammation, altered synaptic proteins and insulin/IGF-1 (insulin-like growth factor-1) signaling, and increased hyperphosphorylated tau in the brain. The most prominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the 3xTg-AD mouse it was elevation of hyperphosphorylated tau. These observations demonstrate the behavioral and neuropathological similarities and differences between the icv-STZ mouse and the 3xTg-AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.

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Acknowledgments

We thank Ms. J. Murphy for secretarial assistance. This work was supported in part by the New York State Office for People with Developmental Disabilities as well as grants from the National Institutes of Health (R01 AG027429, R03 TW008123), the U.S. Alzheimer’s Association (IIRG-10-170405 and IIRG-10-173154), the National Natural Science Foundation of China (30901386), and the Wuhan Science and Technology Bureau, China (200960323132). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, NY, 10314, USA

    Yanxing Chen, Julie Blanchard, Chun-Ling Dai, Inge Grundke-Iqbal, Khalid Iqbal, Fei Liu & Cheng-Xin Gong

  2. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430022, China

    Yanxing Chen, Zhihou Liang & Shenggang Sun

  3. Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, NY, 10314, USA

    Moon H. Lee

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  1. Yanxing Chen
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Correspondence to Cheng-Xin Gong.

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Yanxing Chen and Zhihou Liang contributed equally to this work.

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Chen, Y., Liang, Z., Blanchard, J. et al. A Non-transgenic Mouse Model (icv-STZ Mouse) of Alzheimer’s Disease: Similarities to and Differences from the Transgenic Model (3xTg-AD Mouse). Mol Neurobiol 47, 711–725 (2013). https://doi.org/10.1007/s12035-012-8375-5

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