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.
Authors	Zhong Zhao, Lap Ho, Jun Wang, Weiping Qin, Eugene D Festa, Charles Mobbs, Patrick Hof, Anne Rocher, Sandra Masur, Vahram Haroutunian, Giulio Maria Pasinetti
Journal	FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 19 Issue 14 Pg. 2081-2 (Dec 2005) ISSN: 1530-6860 [Electronic] United States
PMID	16186174 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Amyloid beta-Peptides CCN2 protein, human CCN2 protein, mouse Enzyme Inhibitors Immediate-Early Proteins Insulin Intercellular Signaling Peptides and Proteins Peptides RNA, Messenger Recombinant Proteins Connective Tissue Growth Factor Proto-Oncogene Proteins c-akt Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse Insulysin
Topics	Aged, 80 and over Alzheimer Disease (pathology) Amyloid Precursor Protein Secretases Amyloid beta-Peptides (metabolism, physiology) Animal Feed Animals Aspartic Acid Endopeptidases Brain (metabolism, pathology) Connective Tissue Growth Factor Diabetes Mellitus, Type 2 (pathology) Disease Models, Animal Disease Progression Endopeptidases (metabolism) Enzyme Inhibitors (pharmacology) Enzyme-Linked Immunosorbent Assay Female Fibrosis Gene Expression Regulation Genome Humans Immediate-Early Proteins (biosynthesis, physiology) Insulin (metabolism) Insulin Resistance Insulysin (metabolism) Intercellular Signaling Peptides and Proteins (biosynthesis, physiology) MAP Kinase Signaling System Male Mice Mice, Transgenic Mitogen-Activated Protein Kinase 1 (metabolism) Mitogen-Activated Protein Kinase 3 (metabolism) Models, Biological Neurofibrillary Tangles (metabolism) Neurons (metabolism, pathology) Oligonucleotide Array Sequence Analysis Peptides (chemistry) Phosphatidylinositol 3-Kinases (metabolism) Plaque, Amyloid (metabolism) Proto-Oncogene Proteins c-akt (metabolism) RNA, Messenger (metabolism) Recombinant Proteins (chemistry) Reverse Transcriptase Polymerase Chain Reaction Species Specificity Time Factors

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