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Review ArticleReview Article

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

Ian Clark, Craig Atwood, Richard Bowen, Gilberto Paz-Filho and Bryce Vissel
David R. Sibley, ASSOCIATE EDITOR
Pharmacological Reviews October 2012, 64 (4) 1004-1026; DOI: https://doi.org/10.1124/pr.112.005850
Ian Clark
Research School of Biology, Australian National University, Canberra, Australia (I.C.); Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin (C.A.); School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, Australia (C.A.); OTB Research, Charleston, South Carolina (R.B.); John Curtin School of Medical Research, Australian National University, Canberra, Australia (G.P.-F.); and the Neurodegeneration Research Group, Garvan Institute of Medical Research, Sydney, Australia (B.V.)
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Craig Atwood
Research School of Biology, Australian National University, Canberra, Australia (I.C.); Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin (C.A.); School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, Australia (C.A.); OTB Research, Charleston, South Carolina (R.B.); John Curtin School of Medical Research, Australian National University, Canberra, Australia (G.P.-F.); and the Neurodegeneration Research Group, Garvan Institute of Medical Research, Sydney, Australia (B.V.)
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Richard Bowen
Research School of Biology, Australian National University, Canberra, Australia (I.C.); Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin (C.A.); School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, Australia (C.A.); OTB Research, Charleston, South Carolina (R.B.); John Curtin School of Medical Research, Australian National University, Canberra, Australia (G.P.-F.); and the Neurodegeneration Research Group, Garvan Institute of Medical Research, Sydney, Australia (B.V.)
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Gilberto Paz-Filho
Research School of Biology, Australian National University, Canberra, Australia (I.C.); Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin (C.A.); School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, Australia (C.A.); OTB Research, Charleston, South Carolina (R.B.); John Curtin School of Medical Research, Australian National University, Canberra, Australia (G.P.-F.); and the Neurodegeneration Research Group, Garvan Institute of Medical Research, Sydney, Australia (B.V.)
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Bryce Vissel
Research School of Biology, Australian National University, Canberra, Australia (I.C.); Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin (C.A.); School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, Australia (C.A.); OTB Research, Charleston, South Carolina (R.B.); John Curtin School of Medical Research, Australian National University, Canberra, Australia (G.P.-F.); and the Neurodegeneration Research Group, Garvan Institute of Medical Research, Sydney, Australia (B.V.)
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David R. Sibley
Research School of Biology, Australian National University, Canberra, Australia (I.C.); Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin (C.A.); School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, Australia (C.A.); OTB Research, Charleston, South Carolina (R.B.); John Curtin School of Medical Research, Australian National University, Canberra, Australia (G.P.-F.); and the Neurodegeneration Research Group, Garvan Institute of Medical Research, Sydney, Australia (B.V.)
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Abstract

The evident limitations of the amyloid theory of the pathogenesis of Alzheimer's disease are increasingly putting alternatives in the spotlight. We argue here that a number of independently developing approaches to therapy—including specific and nonspecific anti-tumor necrosis factor (TNF) agents, apolipoprotein E mimetics, leptin, intranasal insulin, the glucagon-like peptide-1 mimetics and glycogen synthase kinase-3 (GSK-3) antagonists—are all part of an interlocking chain of events. All these approaches inform us that inflammation and thence cerebral insulin resistance constitute the pathway on which to focus for a successful clinical outcome in treating this disease. The key link in this chain presently absent is a recognition by Alzheimer's research community of the long-neglected history of TNF induction of insulin resistance. When this is incorporated into the bigger picture, it becomes evident that the interventions we discuss are not competing alternatives but equally valid approaches to correcting different parts of the same pathway to Alzheimer's disease. These treatments can be expected to be at least additive, and conceivably synergistic, in effect. Thus the inflammation, insulin resistance, GSK-3, and mitochondrial dysfunction hypotheses are not opposing ideas but stages of the same fundamental, overarching, pathway of Alzheimer's disease pathogenesis. The insight this provides into progenitor cells, including those involved in adult neurogenesis, is a key part of this approach. This pathway also has therapeutic implications for other circumstances in which brain TNF is pathologically increased, such as stroke, traumatic brain injury, and the infectious disease encephalopathies.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    http://dx.doi.org/10.1124/pr.112.005850.

  • © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 64 (4)
Pharmacological Reviews
Vol. 64, Issue 4
1 Oct 2012
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Review ArticleReview Article

TNF CAUSES INSULIN RESISTANCE: IMPLICATIONS FOR AD

Ian Clark, Craig Atwood, Richard Bowen, Gilberto Paz-Filho and Bryce Vissel
Pharmacological Reviews October 1, 2012, 64 (4) 1004-1026; DOI: https://doi.org/10.1124/pr.112.005850

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Review ArticleReview Article

TNF CAUSES INSULIN RESISTANCE: IMPLICATIONS FOR AD

Ian Clark, Craig Atwood, Richard Bowen, Gilberto Paz-Filho and Bryce Vissel
Pharmacological Reviews October 1, 2012, 64 (4) 1004-1026; DOI: https://doi.org/10.1124/pr.112.005850
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  • Article
    • Abstract
    • I. Introduction
    • II. Gonadotropins, Sex Steroids, Tumor Necrosis Factor, and Alzheimer's Disease
    • III. Tumor Necrosis Factor and Alzheimer's Disease
    • IV. Tumor Necrosis Factor, Amyloid β, and τ
    • V. Insulin
    • VI. Tumor Necrosis Factor and Glycogen Synthase Kinase-3
    • VII. Tumor Necrosis Factor and Mitochondrial Dysfunction
    • VIII. Tumor Necrosis Factor and Progenitor Cells
    • IX. Streptozotocin
    • X. The Broader Picture—Stroke, Traumatic Brain Injury, and Infectious Disease
    • XI. Therapeutic Implications
    • XII. Conclusions
    • Authorship Contributions
    • Footnotes
    • References
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