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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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“deficits, plaque pathology, and tau hyperphosphorylation [90,91], indicating that STZ renders the brain more suscep-”
Background
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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