Insulin-resistant brain state: The culprit in sporadic Alzheimer's disease?
Open accessAbstract
Severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease (sAD) pathology. Indeed, the "insulin-resistant brain state" has been hypothesized to form the core of the neurodegenerative events that occur in sAD. In this vein, intracerebroventricular administration of subdiabetogenic doses of streptozotocin (STZ) in rats can induce an insulin-resistant brain state, which is proposed as a suitable experimental model of sAD. This review highlights the involvement of disturbed brain insulin metabolism in sAD etiopathogenesis. Furthermore, current knowledge demonstrates that central STZ administration produces brain pathology and behavioral changes that resemble changes found in sAD patients. The STZ-intracerebroventricularly treated rat represents a promising experimental tool in this field by providing new insights concerning early brain alterations in sAD, which can be translated in novel etiopathogenic and therapeutic approaches in this disease.
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Lower levels of Akt activation weaken the inhibition of glycogen synthase kinase-3, which in turn positively affects phosphorylation of tau protein and production of Aβ.
“Lower levels of Akt activation weaken the inhibition of glycogen synthase kinase-3 (GSK-3), which in turn positively affects the phosphorylation of tau protein and the production of Aβ.333,338,339”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [333]
In “Insulin function and signaling in the brain” (page unavailable), the review says activated PI3-K/Akt inhibits GSK-3, GSK-3β phosphorylates tau, and GSK-3α regulates Aβ peptide formation. It does not establish that reduced Akt activation increases Aβ production specifically; the Aβ evidence describes regulation of formation or accumulation rather than that full directional chain. (LLM, conf=0.82)
Experimental — accuracy not yet measuredGlucose metabolism amelioration in the CNS is supposed to improve cognitive decline in early and late amnestic MCI patients or prevent cognitive decline in obese people.
“Glucose metabolism amelioration in the Central Nervous System (CNS) is supposed to improve the cognitive decline of early and late amnestic Mild Cognitive Impairment patients or prevent the cognitive decline in obese people [3,105,106].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [106]
The Introduction (page unavailable) reports improved cognitive performance after insulin administration in people with Alzheimer’s disease, and the Conclusions link impaired brain glucose metabolism to cognitive dysfunction. The paper does not establish that improving CNS glucose metabolism benefits early- or late-amnestic MCI patients or prevents cognitive decline in obese people; searches for those populations found no matching passage. (LLM, conf=0.82)
Experimental — accuracy not yet measuredGlucose metabolism amelioration in CNS is supposed to improve the cognitive decline of aMCI patients or prevent the cognitive decline in obese people.
“Glucose metabolism amelioration in CNS is supposed to improve the cognitive decline of aMCI patients or prevent the cognitive decline in obese people [163,167].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [167]
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References 159 · Cited by 212
Research works printed but not linked: 1
- Blokland A Jolles J Spatial learning deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin Pharmacol. Biochem. Behav 1993 44 491 494 8446683
- Authors
- Correia, S. C., Santos, R. X., Perry, G., Zhu, X., Moreira, P. I., & Smith, M. A.
- Affiliations
- University of Coimbra (PT)
- Centro de Neurociências e Biologia Celular (PT)
- The University of Texas at San Antonio (US)
- Case Western Reserve University (US)
- Corresponding author
- Moreira, Paula I.
- Smith, Mark A.
- Venue
- Ageing Research Reviews
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 10
- Issue
- 2
- Pages
- 264-273
- ISSN
- 1568-1637 (ISSN-L)
- PMC
- PMC3056939
- OpenAlex
- W2000115724
- Cited by
- 212
- References
- 159
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 9 · 2023: 8 · 2022: 11 · 2021: 10 · 2020: 18 · 2019: 15 · 2018: 18 · 2017: 17 · 2016: 9 · 2015: 24 · 2014: 19 · 2013: 19 · 2012: 17
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Ageing Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AG028679)
- National Institute on Aging (AG028679, AG 031852, R01AG028679, R01AG031852)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- sporadic Alzheimer's disease, insulin resistance, brain insulin signaling, brain glucose metabolism, streptozotocin, intracerebroventricular administration, streptozotocin-induced Alzheimer's disease model, neurodegeneration, behavior change
- MeSH terms
- Alzheimer Disease, Animals, Blood Glucose, Brain, Diabetes Mellitus, Experimental, Energy Metabolism, Injections, Intraventricular, Insulin, Streptozocin, Signal Transduction, Rats, Wistar, Oxidative Stress, Rats
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