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Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance- associated promotion of Alzheimer's disease beta-amyloid neuropathology.

Abstract

The goal of this study was to further explore potential mechanisms through which diabetogenic dietary conditions that result in promotion of insulin resistance (IR), a feature of non-insulin dependant diabetes mellitus (type-2 diabetes), may influence Alzheimer's disease (AD). Using genome-wide array technology, we found that connective tissue growth factor (CTGF), a gene product described previously for its involvement in diabetic fibrosis, is elevated in brain tissue in an established mouse model of diet-induced IR. With this evidence we continued to explore the regulation of CTGF in postmortem AD brain tissue and found that CTGF expression correlated with the progression of AD clinical dementia and amyloid neuritic plaque (NP) neuropathology, but not neurofibrillary tangle (NFT) deposition. Consistent with this evidence, we also found that exposure of Tg2576 mice (a model AD-type amyloid neuropathology) to a diabetogenic diet that promotes IR results in a ~2-fold elevation in CTGF steady-state levels in the brain, coincident with a commensurate promotion of AD-type amyloid plaque burden. Finally, using in vitro cellular models of amyloid precursor protein (APP)-processing and Abeta generation/clearance, we confirmed that human recombinant (hr)CTGF may increase Abeta1-40 and Abeta1-42 peptide steady-state levels, possibly through a mechanism that involves gamma-secretase activation and decreased insulin-degrading enzyme (IDE) steady-state levels in a MAP kinase (MAPK)/ phosphatidylinositol 3-kinase (PI-3K)/protein kinase-B (AKT)1-dependent manner. The findings in this study tentatively suggest that increased CTGF expression in the brain might be a novel biological predicative factor of AD clinical progression and neuropathology in response to dietary regimens promoting IR conditions.

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  • Authors+Show Affiliations

    ,

    Neuroinflammation Research Laboratories, Mount Sinai School of Medicine, New York, NY 10029, USA.

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    Source

    MeSH

    Aged, 80 and over
    Alzheimer Disease
    Amyloid Precursor Protein Secretases
    Amyloid beta-Peptides
    Animal Feed
    Animals
    Aspartic Acid Endopeptidases
    Brain
    Connective Tissue Growth Factor
    Diabetes Mellitus, Type 2
    Disease Models, Animal
    Disease Progression
    Endopeptidases
    Enzyme Inhibitors
    Enzyme-Linked Immunosorbent Assay
    Female
    Fibrosis
    Gene Expression Regulation
    Genome
    Humans
    Immediate-Early Proteins
    Insulin
    Insulin Resistance
    Insulysin
    Intercellular Signaling Peptides and Proteins
    MAP Kinase Signaling System
    Male
    Mice
    Mice, Transgenic
    Mitogen-Activated Protein Kinase 1
    Mitogen-Activated Protein Kinase 3
    Models, Biological
    Neurofibrillary Tangles
    Neurons
    Oligonucleotide Array Sequence Analysis
    Peptides
    Phosphatidylinositol 3-Kinases
    Plaque, Amyloid
    Proto-Oncogene Proteins c-akt
    RNA, Messenger
    Recombinant Proteins
    Reverse Transcriptase Polymerase Chain Reaction
    Species Specificity
    Time Factors

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    16186174

    Citation

    Zhao, Zhong, et al. "Connective Tissue Growth Factor (CTGF) Expression in the Brain Is a Downstream Effector of Insulin Resistance- Associated Promotion of Alzheimer's Disease Beta-amyloid Neuropathology." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 19, no. 14, 2005, pp. 2081-2.
    Zhao Z, Ho L, Wang J, et al. Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance- associated promotion of Alzheimer's disease beta-amyloid neuropathology. FASEB J. 2005;19(14):2081-2.
    Zhao, Z., Ho, L., Wang, J., Qin, W., Festa, E. D., Mobbs, C., ... Pasinetti, G. M. (2005). Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance- associated promotion of Alzheimer's disease beta-amyloid neuropathology. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 19(14), pp. 2081-2.
    Zhao Z, et al. Connective Tissue Growth Factor (CTGF) Expression in the Brain Is a Downstream Effector of Insulin Resistance- Associated Promotion of Alzheimer's Disease Beta-amyloid Neuropathology. FASEB J. 2005;19(14):2081-2. PubMed PMID: 16186174.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance- associated promotion of Alzheimer's disease beta-amyloid neuropathology. AU - Zhao,Zhong, AU - Ho,Lap, AU - Wang,Jun, AU - Qin,Weiping, AU - Festa,Eugene D, AU - Mobbs,Charles, AU - Hof,Patrick, AU - Rocher,Anne, AU - Masur,Sandra, AU - Haroutunian,Vahram, AU - Pasinetti,Giulio Maria, Y1 - 2005/09/26/ PY - 2005/9/28/pubmed PY - 2006/2/28/medline PY - 2005/9/28/entrez SP - 2081 EP - 2 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. VL - 19 IS - 14 N2 - The goal of this study was to further explore potential mechanisms through which diabetogenic dietary conditions that result in promotion of insulin resistance (IR), a feature of non-insulin dependant diabetes mellitus (type-2 diabetes), may influence Alzheimer's disease (AD). Using genome-wide array technology, we found that connective tissue growth factor (CTGF), a gene product described previously for its involvement in diabetic fibrosis, is elevated in brain tissue in an established mouse model of diet-induced IR. With this evidence we continued to explore the regulation of CTGF in postmortem AD brain tissue and found that CTGF expression correlated with the progression of AD clinical dementia and amyloid neuritic plaque (NP) neuropathology, but not neurofibrillary tangle (NFT) deposition. Consistent with this evidence, we also found that exposure of Tg2576 mice (a model AD-type amyloid neuropathology) to a diabetogenic diet that promotes IR results in a ~2-fold elevation in CTGF steady-state levels in the brain, coincident with a commensurate promotion of AD-type amyloid plaque burden. Finally, using in vitro cellular models of amyloid precursor protein (APP)-processing and Abeta generation/clearance, we confirmed that human recombinant (hr)CTGF may increase Abeta1-40 and Abeta1-42 peptide steady-state levels, possibly through a mechanism that involves gamma-secretase activation and decreased insulin-degrading enzyme (IDE) steady-state levels in a MAP kinase (MAPK)/ phosphatidylinositol 3-kinase (PI-3K)/protein kinase-B (AKT)1-dependent manner. The findings in this study tentatively suggest that increased CTGF expression in the brain might be a novel biological predicative factor of AD clinical progression and neuropathology in response to dietary regimens promoting IR conditions. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/16186174/Connective_tissue_growth_factor__CTGF__expression_in_the_brain_is_a_downstream_effector_of_insulin_resistance__associated_promotion_of_Alzheimer's_disease_beta_amyloid_neuropathology_ L2 - http://www.fasebj.org/doi/full/10.1096/fj.05-4359fje?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -