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

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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  • Authors+Show Affiliations

    , , , , , , , ,

    Institute of Biomedicine and Molecular Immunology CNR, via Ugo La Malfa 153, 90146 Palermo, Italy. marta.dicarlo@ibim.cnr.it.

    Source

    Current Alzheimer research 12:8 2015 pg 723-35

    MeSH

    Alzheimer Disease
    Amyloid Precursor Protein Secretases
    Amyloidogenic Proteins
    Animals
    Brain
    Case-Control Studies
    Cytokines
    Diet, High-Fat
    Disease Models, Animal
    Gene Expression Regulation
    Glycogen Synthase Kinase 3
    Glycogen Synthase Kinase 3 beta
    Insulin
    Insulin Resistance
    Male
    Mice
    Mice, Inbred C57BL
    Obesity
    Oxidative Stress
    Receptor, Insulin
    Signal Transduction
    Time Factors

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    26159189

    Citation

    Nuzzo, Domenico, et al. "Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer's Disease." Current Alzheimer Research, vol. 12, no. 8, 2015, pp. 723-35.
    Nuzzo D, Picone P, Baldassano S, et al. Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer's Disease. Curr Alzheimer Res. 2015;12(8):723-35.
    Nuzzo, D., Picone, P., Baldassano, S., Caruana, L., Messina, E., Marino Gammazza, A., ... Di Carlo, M. (2015). Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer's Disease. Current Alzheimer Research, 12(8), pp. 723-35.
    Nuzzo D, et al. Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer's Disease. Curr Alzheimer Res. 2015;12(8):723-35. PubMed PMID: 26159189.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer's Disease. AU - Nuzzo,Domenico, AU - Picone,Pasquale, AU - Baldassano,Sara, AU - Caruana,Luca, AU - Messina,Elisa, AU - Marino Gammazza,Antonella, AU - Cappello,Francesco, AU - Mulè,Flavia, AU - Di Carlo,Marta, PY - 2015/02/24/received PY - 2015/07/03/accepted PY - 2015/7/11/entrez PY - 2015/7/15/pubmed PY - 2016/7/2/medline SP - 723 EP - 35 JF - Current Alzheimer research JO - Curr Alzheimer Res VL - 12 IS - 8 N2 - 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. SN - 1875-5828 UR - https://www.unboundmedicine.com/medline/citation/26159189/Insulin_Resistance_as_Common_Molecular_Denominator_Linking_Obesity_to_Alzheimer's_Disease_ L2 - http://www.eurekaselect.com/132998/article DB - PRIME DP - Unbound Medicine ER -