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.
Keywords: Adipokines, Alzheimer’s disease, gene expression, inflammation, insulin resistance, mitochondrial dysfunction, obesity.
Current Alzheimer Research
Title:Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease
Volume: 12 Issue: 8
Author(s): Domenico Nuzzo, Pasquale Picone, Sara Baldassano, Luca Caruana, Elisa Messina, Antonella Marino Gammazza, Francesco Cappello, Flavia Mulè and Marta Di Carlo
Affiliation:
Keywords: Adipokines, Alzheimer’s disease, gene expression, inflammation, insulin resistance, mitochondrial dysfunction, obesity.
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.
Export Options
About this article
Cite this article as:
Nuzzo Domenico, Picone Pasquale, Baldassano Sara, Caruana Luca, Messina Elisa, Gammazza Marino Antonella, Cappello Francesco, Mulè Flavia and Carlo Di Marta, Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease, Current Alzheimer Research 2015; 12 (8) . https://dx.doi.org/10.2174/1567205012666150710115506
DOI https://dx.doi.org/10.2174/1567205012666150710115506 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Crossed Cerebellar Diaschisis in Alzheimer’s Disease
Current Alzheimer Research Immunologic Modulations to Enhance Post-Stroke Recovery
Current Immunology Reviews (Discontinued) Tandem Mass Spectrometry Newborn Screening for Inborn Errors of Intermediary Metabolism: Abnormal Profile Interpretation
Current Medicinal Chemistry Recent Highlights on Molecular Hybrids Potentially Useful in Central Nervous System Disorders
Mini-Reviews in Medicinal Chemistry Engineered Probiotic and Prebiotic Nutraceutical Supplementations in Combating Non-communicable Disorders: A Review
Current Pharmaceutical Biotechnology Nicotinic Acetylcholine Receptors as Drug Targets
Current Drug Targets - CNS & Neurological Disorders PET Imaging in Clinical Drug Abuse Research
Current Pharmaceutical Design Contribution of Inflammatory Processes to Nerve Cell Toxicity by Bilirubin and Efficacy of Potential Therapeutic Agents
Current Pharmaceutical Design Takotsubo Cardiomyopathy: What we have Learned in the Last 25 Years? (A Comparative Literature Review)
Current Cardiology Reviews Pharmacological Uses of the Plants Belonging to the Genus <i>Commiphora</i>
Cardiovascular & Hematological Agents in Medicinal Chemistry The Chemistry and Bio-Medicinal Significance of Pyrimidines & Condensed Pyrimidines
Current Topics in Medicinal Chemistry Potential Strategies for Minimizing Mechanism-Based Inhibition of Cytochrome P450 3A4
Current Pharmaceutical Design Editorial [Hot Topic: PET and SPECT in Drug Evaluation and Drug Design Imaging Inflammatory Processes, Tumors, and the Endocannabinoid System(Executive Editor: Aren van Waarde)]
Current Pharmaceutical Design Research Review: Childhood Maltreatment and Executive Functioning During Adolescence
Adolescent Psychiatry Organotypic Cultures as Tool to Test Long-Term Effects of Chemicals on the Nervous System
Current Medicinal Chemistry Use of Antiepileptic Drugs for Hyperkinetic Movement Disorders
Current Neuropharmacology Bioinformatics and Drug Discovery
Current Topics in Medicinal Chemistry Targeting PPAR Isoforms Following CNS Injury
Current Drug Targets Neurological Concepts in Ancient Greek Medicine
Current Aging Science Fibromyalgia: The Prototypical Central Sensitivity Syndrome
Current Rheumatology Reviews