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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged, 80 and over
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Alzheimer Disease / pathology*
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Amyloid Precursor Protein Secretases
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Peptides / physiology*
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Animal Feed
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Animals
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Aspartic Acid Endopeptidases
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Brain / metabolism*
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Brain / pathology
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Connective Tissue Growth Factor
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Diabetes Mellitus, Type 2 / pathology
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Disease Models, Animal
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Disease Progression
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Endopeptidases / metabolism
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Enzyme Inhibitors / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Female
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Fibrosis
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Gene Expression Regulation
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Genome
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Humans
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Immediate-Early Proteins / biosynthesis*
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Immediate-Early Proteins / physiology*
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Insulin / metabolism
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Insulin Resistance*
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Insulysin / metabolism
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Intercellular Signaling Peptides and Proteins / biosynthesis*
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Intercellular Signaling Peptides and Proteins / physiology*
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MAP Kinase Signaling System
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Male
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Mice
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Mice, Transgenic
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Biological
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Neurofibrillary Tangles / metabolism
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Neurons / metabolism
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Neurons / pathology
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Oligonucleotide Array Sequence Analysis
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Peptides / chemistry
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Phosphatidylinositol 3-Kinases / metabolism
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Plaque, Amyloid / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / metabolism
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Recombinant Proteins / chemistry
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Reverse Transcriptase Polymerase Chain Reaction
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Species Specificity
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Time Factors
Substances
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Amyloid beta-Peptides
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CCN2 protein, human
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CCN2 protein, mouse
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Enzyme Inhibitors
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Immediate-Early Proteins
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Insulin
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Intercellular Signaling Peptides and Proteins
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Peptides
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RNA, Messenger
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Recombinant Proteins
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Connective Tissue Growth Factor
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse
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Insulysin