Antiapoptotic Activity of Alzheimer Abeta

Summary

Principal Investigator: CRAIG STEPHEN ATWOOD
Abstract: Alzheimer's disease (AD) is a debilitating neurodegenerative disease that is characterized by neuronal cell loss and the deposition of protein aggregates. These neuropathological parameters are correlated with the presence of numerous markers of oxidative stress in the cell bodies of neurons suggesting the involvement of oxidative mechanisms in neuronal cell loss and/or protein deposition. Although the sources of the reactive oxygen species (ROS) leading to this oxidative stress have not been clarified, the brain responds to this chronic oxidative challenge by upregulating antioxidant defense systems (eg. increasing SOD1 and glutathione peroxidase expression). We now have three lines of evidence indicating that the increased generation of Abeta in AD also may be a compensatory response to oxidative stress that prevents neuronal apoptosis. Firstly, we have determined from in vitro studies that Abeta has significant antioxidant (superoxide dismutase) activity, secondly, that nanomolar concentrations of Abeta block apoptosis of neurons following trophic factor withdrawal, and thirdly that the Abeta amyloid burden of the AD-affected brain is significantly negatively correlated with oxidative stress markers. In support of these findings, we find fewer oxidative modifications in amyloid deposits and neurofibrillary tangles compared with the cell bodies of the neurons of AD-affected brains. Together, these compelling data provide a plausible physiological explanation for the increased generation of Abeta in AD and following head trauma. We hypothesize that as the disease progresses, the chronic overproduction of hydrogen peroxide by neuronal cells, microglia and Abeta amyloid deposits may overwhelm the antioxidant defense systems of the aging brain with the end result that ROS promote the apoptotic demise. Thus, the novel aspect of our hypothesis is the recognition that Abeta generation may be a form of pleiotrophic antagonism, whereby Abeta may be physiologically purposive under "normal" conditions (i.e. moderately increased concentrations of superoxide and/or high reducing equivalents), but may promote neuronal cell death under abnormal conditions (i.e. high concentrations of superoxide and Abeta that lead to excess hydrogen peroxide/low reducing equivalents). The proposed studies will therefore examine the generation of Abeta as a compensatory mechanism to oxidative stress that is both antioxidant and anti-apoptotic in nature while testing whether overwhelming oxidative challenges promote apoptosis. We also will test whether oxidative stress induces neurons to re-enter the cell cycle as a mechanism leading to cell death.
Funding Period: 2001-06-01 - 2005-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Alzheimer's disease: the impact of age-related changes in reproductive hormones
    C S Atwood
    Section of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin Madison, Veterans Administration Hospital, Madison, Wisconsin 53705, USA
    Cell Mol Life Sci 62:255-6. 2005
  2. pmc Identification of a gonadotropin-releasing hormone receptor orthologue in Caenorhabditis elegans
    Sivan Vadakkadath Meethal
    Section of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin and Geriatric Research, Education and Clinical Center, Veterans Administration Hospital, Madison, WI 53705, USA
    BMC Evol Biol 6:103. 2006
  3. ncbi Human neurons express type I GnRH receptor and respond to GnRH I by increasing luteinizing hormone expression
    Andrea C Wilson
    Department of Pathology and Laboratory Medicine, Veterans Administration Hospital, University of Wisconsin, 2500 Overlook Terrace, Madison, Wisconsin 53705, USA
    J Endocrinol 191:651-63. 2006
  4. ncbi Luteinizing hormone receptor mediates neuronal pregnenolone production via up-regulation of steroidogenic acute regulatory protein expression
    Tianbing Liu
    Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53705, USA
    J Neurochem 100:1329-39. 2007
  5. ncbi Increased expression of the remodeling- and tumorigenic-associated factor osteopontin in pyramidal neurons of the Alzheimer's disease brain
    John K Wung
    Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
    Curr Alzheimer Res 4:67-72. 2007
  6. ncbi Iron homeostasis is maintained in the brain, but not the liver, following mild hypoxia
    Glenda M Bishop
    Institute of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
    Redox Rep 12:257-66. 2007

Scientific Experts

  • CRAIG STEPHEN ATWOOD
  • Sivan Vadakkadath Meethal
  • Glenda M Bishop
  • Andrea C Wilson
  • John K Wung
  • Tianbing Liu
  • George Perry
  • Mark A Smith
  • Richard L Bowen
  • Mehul A Trivedi
  • Jay Wimalasena
  • Aaron Kowalski
  • Sterling C Johnson
  • Peggy L R Harris
  • Joseph C Lamanna
  • David T Denhardt
  • M Shahriar Salamat
  • Ryan J Haasl
  • Ei Terasawa
  • Sivan Vadakkadath Meethal
  • Kelly M Roche
  • Anjali Karande

Detail Information

Publications6

  1. ncbi Alzheimer's disease: the impact of age-related changes in reproductive hormones
    C S Atwood
    Section of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin Madison, Veterans Administration Hospital, Madison, Wisconsin 53705, USA
    Cell Mol Life Sci 62:255-6. 2005
  2. pmc Identification of a gonadotropin-releasing hormone receptor orthologue in Caenorhabditis elegans
    Sivan Vadakkadath Meethal
    Section of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin and Geriatric Research, Education and Clinical Center, Veterans Administration Hospital, Madison, WI 53705, USA
    BMC Evol Biol 6:103. 2006
    ..This study examined whether GPCRs orthologous to human gonadotropin-releasing hormone receptor (GnRHR) exist in C. elegans...
  3. ncbi Human neurons express type I GnRH receptor and respond to GnRH I by increasing luteinizing hormone expression
    Andrea C Wilson
    Department of Pathology and Laboratory Medicine, Veterans Administration Hospital, University of Wisconsin, 2500 Overlook Terrace, Madison, Wisconsin 53705, USA
    J Endocrinol 191:651-63. 2006
    ..Post-reproductive surges in GnRH I secretion may explain the accumulation of LH in pyramidal neurons of the aged human and rat...
  4. ncbi Luteinizing hormone receptor mediates neuronal pregnenolone production via up-regulation of steroidogenic acute regulatory protein expression
    Tianbing Liu
    Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53705, USA
    J Neurochem 100:1329-39. 2007
    ....
  5. ncbi Increased expression of the remodeling- and tumorigenic-associated factor osteopontin in pyramidal neurons of the Alzheimer's disease brain
    John K Wung
    Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
    Curr Alzheimer Res 4:67-72. 2007
    ....
  6. ncbi Iron homeostasis is maintained in the brain, but not the liver, following mild hypoxia
    Glenda M Bishop
    Institute of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
    Redox Rep 12:257-66. 2007
    ..Together, these results indicate that there is a tighter regulation of iron metabolism in the brain than the liver, which limits the redistribution of Fe3+ following hypoxia...