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
-
Spatio-Temporal Fluctuations of Neural Dynamics in Mild Cognitive Impairment and Alzheimer’s Disease
Current Alzheimer Research Nanomedicines for Brain Targeting: A Patent Review
Recent Patents on Nanomedicine mTOR, a Potential Target to Treat Autism Spectrum Disorder
CNS & Neurological Disorders - Drug Targets Subject Index to Volume 3
Current Drug Targets - CNS & Neurological Disorders Catatonia: A Brief Update
Current Psychiatry Reviews Sodium Channel Toxins - Receptor Targeting and Therapeutic Potential
Current Medicinal Chemistry Nose to Brain Delivery of Nanoformulations for Neurotherapeutics in Parkinson’s Disease: Defining the Preclinical, Clinical and Toxicity Issues
Current Drug Delivery AMPA Receptor Positive Allosteric Modulators: Potential for the Treatment of Neuropsychiatric and Neurological Disorders
Current Topics in Medicinal Chemistry Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites, Immuno-inflammation, Autoimmunity and the Amygdala
Current Neuropharmacology Citrus Peel Extract Attenuates Acute Cyanide Poisoning-Induced Seizures and Oxidative Stress in Rats
CNS & Neurological Disorders - Drug Targets ATP-Binding Cassette Transporters at the Blood-Brain Barrier in Ischaemic Stroke
Current Pharmaceutical Design Clinical Pharmacokinetics of Retigabine/Ezogabine
Current Clinical Pharmacology Effect of the Surfactant and Liquid Lipid Type in the Physico-chemical Characteristics of Beeswax-based Nanostructured Lipid Carrier (NLC) of Metformin
Pharmaceutical Nanotechnology Editorial [Hot Topic: New Ligands at 5-HT and DA Receptors for the Treatment of Neuropsychiatric Disorders (Guest Editor: Giuseppe Di Giovanni) ]
Current Topics in Medicinal Chemistry QSAR Modeling of Histamine H3R Antagonists/inverse Agonists as Future Drugs for Neurodegenerative Diseases
Current Neuropharmacology Cyclooxygenase-2 in Synaptic Signaling
Current Pharmaceutical Design Cell-based Treatment of Cerebral Palsy: Still a Long Way Ahead
Current Stem Cell Research & Therapy Comparison of HPLC-DAD and UPLC-MS/MS in Monitoring Serum Concentration of Lamotrigine
Current Pharmaceutical Analysis Triazino-caffeine Derivatives by Intramolecular Cyclization: Synthesis, Characterization and Antimicrobial Studies
Letters in Organic Chemistry Transcranial Magnetic Stimulation on Rodent Models
CNS & Neurological Disorders - Drug Targets