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Cited by 119Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.

Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer‘s Disease

Nuzzo, Domenico, Picone, Pasquale, Baldassano, Sara, Caruana, Luca, Messina, Elisa, Gammazza, Antonella, Cappello, Francesco, Mulè, Flavia, Carlo, Marta·2015·Current Alzheimer Research
DOI 10.2174/1567205012666150710115506
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Abstract

Alzheimer's disease (AD) is an aging-related multi-factorial disorder to which metabolic factors contribute at what has canonically been considered a centrally mediated process. Although the exact underlying mechanisms are still unknown, obesity is recognized as a risk factor for AD and the condition of insulin resistance seems to be the link between the two pathologies. Using mice with high fat diet (HFD) obesity we dissected the molecular mechanisms shared by the two disorders. Brains of HFD fed mice showed elevated levels of APP and Aβ40/Aβ42 together with BACE, GSK3β and Tau proteins involved in APP processing and Aβ accumulation. Immunofluorescence, Thioflavin T staining experiments, confirmed increased Aβ generation, deposition in insoluble fraction and plaques formation in both the hippocampus and the cerebral cortex of HFD mice. Presence of Aβ40/Aβ42 in the insoluble fraction was also shown by ELISA assay. Brain insulin resistance was demonstrated by reduced presence of insulin receptor (IRs) and defects in Akt-Foxo3a insulin signaling. We found reduced levels of phospho-Akt and increased levels of Foxo3a in the nuclei of neurons where proapototic genes were activated. Dysregulation of different genes related to insulin resistance, especially those involved in inflammation and adipocytokines synthesis were analyzed by Profiler PCR array. Further, HFD induced oxidative stress, mitochondrial dysfunction and dynamics as demonstrated by expression of biomarkers involved in these processes. Here, we provide evidence that obesity and AD markers besides insulin resistance are associated with inflammation, adipokine dyshomeostasis, oxidative stress and mitochondrial dysfunction, all mechanisms leading to neurodegeneration.

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Metadata

Authors
Nuzzo, D., Picone, P., Baldassano, S., Caruana, L., Messina, E., Gammazza, A., Cappello, F., Mulè, F., & Carlo, M.
Affiliations
  • National Research Council (IT)
  • Istituto di Biomedicina e di Immunologia Molecolare Alberto Monroy (IT)
ORCID
Venue
Current Alzheimer Research
Publisher
Bentham Science Publishers Ltd.
Published
2015-09-11
Volume
12
Issue
8
Pages
723-735
ISSN
1567-2050 (ISSN-L)
DOI
10.2174/1567205012666150710115506
OpenAlex
W831032665
Cited by
119
References
60
Citations by year
2026: 4 · 2025: 6 · 2024: 9 · 2023: 9 · 2022: 11 · 2021: 6 · 2020: 13 · 2019: 19 · 2018: 15 · 2017: 10 · 2016: 16 · 2015: 1
FWCI
10.33
Type
journal article
Language
en
Open access
closed
Locations
  • Current Alzheimer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
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, Alzheimer's disease, obesity, high-fat diet, amyloid-beta, APP processing, BACE, GSK3β, tau protein, insulin receptor, neuroinflammation, adipokines, oxidative stress, mitochondrial dysfunction, neurodegeneration, amyloid plaques
MeSH terms
Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Gene Expression Regulation, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Obesity, Receptor, Insulin, Time Factors, Signal Transduction, Case-Control Studies, Cytokines, Oxidative Stress, Glycogen Synthase Kinase 3, Mice, Amyloid Precursor Protein Secretases, Amyloidogenic Proteins, Diet, High-Fat

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