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Insulin-Resistant Brain State after Intracerebroventricular Streptozotocin Injection Exacerbates Alzheimer-like Changes in Tg2576 AβPP-Overexpressing Mice
Abstract
For studying rare hereditary Alzheimer's disease (AD), transgenic (Tg) animal models overexpressing amyloid-beta protein precursor (AbetaPP) followed by increased amyloid-beta (Abeta) formation are used. In contrast, sporadic AD has been proposed to start with an insulin-resistant brain state (IRBS).We investigated the effect of IRBS induced by intracerebroventricularly (icv) administered streptozotocin (STZ) on behavior, glycogen synthase kinase-3 (GSK) alpha/beta content, and the formation of AD-like morphological hallmarks Abeta and tau protein in AbetaPP Tg2576 mice. Nine-month-old Tg mice were investigated 6 months after a single icv injection of STZ or placebo. Spatial cognition was analyzed using the Morris water maze test. Soluble and aggregated Abeta40/42 fragments, total and phosphorylated tau protein, and GSK-3alpha/beta were determined by ELISA. Cerebral (immuno)histological analyses were performed. In Tg mice, STZ treatment increased mortality, reduced spatial cognition, and increased cerebral aggregated Abeta fragments, total tau protein, and congophilic amyloid deposits. These changes were associated with decreased GSK-3alpha/beta ratio (phosphorylated/total). A linear negative correlation was detected between Abeta42 and cognition, and between GSK-3alpha/beta ratio and aggregated Abeta40+42. No marked necrotic and apoptotic changes were observed. In conclusion, IRBS may aggravate AD-like changes such as behavioral and increase the formation of pathomorphological AD hallmarks via GSK-3alpha/beta pathway in AbetaPP-overexpressing mice.
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“Experimentally-induced diabetes moreover causes accelerated cognitive failure in AD mouse models (Cao et al., 2007; Ho et al., 2004; Plaschke et al., 2010; Wang et al., 2010).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Plaschke et al., 2010
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Items 101–120 of 120
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Self-citationUniv.- Prof. Dr. med. Siegfried Hoyer 1933–2014
Pf, R. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1220-4 · Cited by 1
“2006, 2011, 2013) and potentiates transgenic models pathology (Plaschke et al. 2010).”
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Self-citationA streptozotocin-induced model of Alzheimer's disease in mice with wild-type human tau
Rudy, C. C. (2014) · The Research Repository @ WVU (West Virginia University) · doi:10.33915/etd.620 · Cited by 1
“In one of the longest timeframes, nine-month-old transgenic mice with a mutation in the Aβ precursor protein showed deficits in the MWM 6 months after ICV-STZ (Plaschke et al., 2010).”
BackgroundThe Janus Face of Insulin in Brain
Duarte, A. I., Candeias, E., Correia, S. C., Santos, R. X., Carvalho, C., Cardoso, S., Plácido, A. I., Santos, M. S., Oliveira, C. R., & Moreira, P. I. (2013) · Wiley eBooks · doi:10.1002/9781118395318.ch5
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Mehran, A. E. (2015) · cIRcle (University of British Columbia) · doi:10.14288/1.0167270
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Villar, M. F. Z. (2018) · El Servicio de Difusión de la Creación Intelectual (National University of La Plata) · doi:10.35537/10915/71572
Tristão‐Pereira, C., Diao, Y., Yin, T., da Silva, A. R., Lanz, B., Pierzchała, K., Poitry‐Yamate, C., & Jelescu, I. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.30.926444
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Riederer, P. F., Bartl, J., Laux, G., & Grünblatt, E. (2013) · Springer eBooks · doi:10.1007/978-1-4614-7264-3_16
Self-citationDiabetes Type II: A Risk Factor for Depression-Parkinson-Alzheimer?
Riederer, P. F., Bartl, J., Laux, G., & Grünblatt, E. (2010) · Springer eBooks · doi:10.1007/978-1-4614-0785-0_14
Self-citationBee Bread Shows Protective Effects in a Streptozotocin-Induced Alzheimer's Disease Rat ModelPreprint
Acun, A. D., Afşar, E., & Kantar, D. (2025) · Research Square · doi:10.21203/rs.3.rs-7268712/v1
Loss of brain insulin production impairs learning and memory in female mice
Baehring, S., O’Leary, T. P., Cen, H. H., Holenka, D., Kim, K., Ajayi, S., Semenov, D., Belmadani, M., Li, H., Mehran, A. E., et al. (2026) · Metabologia · doi:10.1007/s44357-026-00004-8 · Cited by 1
Loss of brain insulin production impairs learning and memory in female micePreprint
Baehring, S., O’Leary, T. P., Cen, H. H., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-7826673/v1
Bee Bread Shows Protective Effects in a Streptozotocin-Induced Alzheimer's Disease Rat Model
Acun, A. D., Afşar, E., & Kantar, D. (2026) · Bratislavské lekárske listy/Bratislava medical journal · doi:10.1007/s44411-026-00490-9
“Intracerebroventricular (ICV) administration of streptozotocin (STZ), a glucosamine-nitrosourea molecule derived from soil bacteria, mimics the neuropathological and metabolic changes of sporadic AD (sAD) [19, 20].”
Silva, V.-F. D., Gayger-Dias, V., Gayger-Dias, V., Sobottka, T. M., Silva, A. C. R., Biolchi, B. C. R., da Silva, L. F., Zasso, N., Weber, F. B., Schimitz, I., et al. (2026) · Neurochemical Research · doi:10.1007/s11064-026-04884-7
“…of action of STZ in the CNS is unknown, this drug is also used to accelerate the appearance of pathognomonic signs of AD (i.e., amyloid plaques) in rodent genetic models of the disease, where it induces the expression of human amyloid precursor protein, which will generate amyloid peptides [12].”
Metadata
- Authors
- Plaschke, K., Kopitz, J., Siegelin, M., Schliebs, R., Salkovic-Petrisic, M., Riederer, P., & Hoyer, S.
- Affiliations
- Heidelberg University (DE)
- Leipzig University (DE)
- Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia
- Universitätsklinikum Würzburg (DE)
- Corresponding author
- Plaschke, Konstanze
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2010-01-07
- Volume
- 19
- Issue
- 2
- Pages
- 691-704
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1802455527
- Cited by
- 118
- References
- 0
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 8 · 2020: 10 · 2019: 3 · 2018: 7 · 2017: 8 · 2016: 8 · 2015: 6 · 2014: 13 · 2013: 13 · 2012: 10
- FWCI
- 8.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- insulin resistance, brain
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Age Factors, Alzheimer Disease, Animals, Avoidance Learning, Brain, Diabetes Mellitus, Experimental, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Injections, Intraventricular, Insulin Resistance, Memory Disorders, Mice, Transgenic, Mutation, Psychomotor Performance, Reaction Time, Streptozocin, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Apoptosis, Maze Learning, In Situ Nick-End Labeling, Glycogen Synthase Kinase 3, Mice, Plaque, Amyloid
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