Intracerebral streptozotocin model of type 3 diabetes: Relevance to sporadic Alzheimer’s disease

Lester-Coll, Nataniel; Rivera, Enrique J.; Soscia, Stephanie J.; Doiron, Kathryn; Wands, Jack R.; de la Monte, Suzanne M.

doi:10.3233/jad-2006-9102

Cited by 467Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Intracerebral streptozotocin model of type 3 diabetes: Relevance to sporadic Alzheimer’s disease

Lester-Coll, Nataniel, Rivera, Enrique J., Soscia, Stephanie J., Doiron, Kathryn, Wands, Jack R., de la Monte, Suzanne M.·2006·Journal of Alzheimer s Disease

DOI 10.3233/jad-2006-9102

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Abstract

The cascade of Alzheimer's disease (AD) neurodegeneration is associated with persistent oxidative stress, mitochondrial dysfunction, impaired energy metabolism, and activation of pro-death signaling pathways. More recently, studies with human postmortem brain tissue linked many of the characteristic molecular and pathological features of AD to reduced expression of the insulin and insulin-like growth factor (IGF) genes and their corresponding receptors. We now demonstrate using an in vivo model of intracerebral Streptozotocin (ic-STZ), that chemical depletion of insulin and IGF signaling mechanisms combined with oxidative injury is sufficient to cause AD-type neurodegeneration. The ic-STZ-injected rats did not have elevated blood glucose levels, and pancreatic architecture and insulin immunoreactivity were similar to control, yet their brains were reduced in size and exhibited neurodegeneration associated with cell loss, gliosis, and increased immunoreactivity for p53, active glycogen synthase kinase 3beta, phospho-tau, ubiquitin, and amyloid-beta. Real time quantitative RT-PCR studies demonstrated that the ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons, oligodendroglia, and choline acetyltransferase, and increased expression of genes encoding glial fibrillary acidic protein, microglia-specific proteins, acetylcholinesterase, tau, and amyloid precursor protein. These abnormalities were associated reduced expression of genes encoding insulin, IGF-II, insulin receptor, IGF-I receptor, and insulin receptor substrate-1, and reduced ligand binding to the insulin and IGF-II receptors. These results demonstrate that many of the characteristic features of AD-type neurodegeneration can be produced experimentally by selectively impairing insulin/IGF functions together with increasing oxidative stress, and support our hypothesis that AD represents a neuro-endocrine disorder associated with brain-specific perturbations in insulin and IGF signaling mechanisms, i.e. Type 3 diabetes.

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AD-like changes have been observed in experimental models of insulin resistance, including animals fed a high fat diet or receiving intracerebral or IP injections of streptozotocin.
“Supporting this idea, AD-like changes have been observed in experimental models of insulin resistance, including animals fed a high fat diet or receiving intracerebral or IP injections of streptozotocin (Cao et al., 2007; Labak et al., 2010; Lester-Coll et al., 2006; Ma et al., 2009; Pratchayasakul et al., 2011; Tong et al., 2009; Zhang et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lester-Coll et al., 2006

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Authors: Lester-Coll, N., Rivera, E. J., Soscia, S. J., Doiron, K., Wands, J. R., & de la Monte, S. M.
Affiliations: Brown University (US)
Departments of Medicine and Pathology, Rhode Island Hospital and Brown Medical School, Providence, RI, USA
ORCID: Lester-Coll, Nataniel
Wands, Jack R.
Venue: Journal of Alzheimer s Disease
Publisher: SAGE Publications
Published: 2006-04-06
Volume: 9
Issue: 1
Pages: 13-33
ISSN: 1387-2877 (ISSN-L)
1875-8908
DOI: 10.3233/jad-2006-9102
OpenAlex: W1546369396
Cited by: 467
References: 93
Citations by year: 2026: 9 · 2025: 16 · 2024: 13 · 2023: 19 · 2022: 18 · 2021: 17 · 2020: 21 · 2019: 26 · 2018: 28 · 2017: 29 · 2016: 34 · 2015: 31 · 2014: 28 · 2013: 37 · 2012: 39
FWCI: 13.04
Type: journal article
Language: en
Open access: closed
Locations: Journal of Alzheimer s Disease (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Alcohol Abuse and Alcoholism (AA-02666, AA-12908, AA-02169, AA11431, R01AA012908)
National Cancer Institute (CA 35711)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: type 3 diabetes, Alzheimer's disease
MeSH terms: Alzheimer Disease, Animals, Brain, Diabetes Mellitus, Experimental, Disease Models, Animal, Humans, Injections, Intraventricular, Insulin, Islets of Langerhans, Receptor, Insulin, Streptozocin, Rats, Long-Evans, Rats

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Intracerebral streptozotocin model of type 3 diabetes: Relevance to sporadic Alzheimer’s disease

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