Copper's Role in Brain LRP-mediated Abeta Efflux and Aging

Summary

Principal Investigator: Rashid Deane
Abstract: DESCRIPTION (provided by applicant): Accumulation of neurotoxic amyloid-[unreadable] (A[unreadable]) species in brain is accelerated in AD. A[unreadable] clearance by rapid transport across the blood-brain-barrier (BBB), requires LRP (low-density lipoprotein receptor-related protein1), the main receptor that clears A[unreadable] from brain in an isoform specific manner. Copper (Cu), the focus of this research proposal, is associated with amyloid plaques in AD brains. It avidly binds A[unreadable] and may promote betasheet conformation, aggregation and toxicity. Cu may reduce A[unreadable] elimination from brain in rabbits, dosed with tracer levels of Cu. Our preliminary data using mice dosed with tracer levels of Cu in their drinking water showed: 1) increased Cu levels and decreased LRP protein levels in brain microvessels, 2) increased brain A[unreadable] levels by reducing its BBB clearance and 3) no significant changes in protein levels of APP, BACE, IDE, NEP or A[unreadable] putative receptors such as PgP and RAGE in brain microvessels. HBEC incubated with Cu (200 nM) had decreased 125I-A[unreadable]42 binding associated with LRP down-regulation, increased LRP nitrotyrosination, and enhanced LRP proteosomal degradation. In contrast, Cu did not affect HBEC-mediated angiogenesis, apoptosis, NF-?B activation. Al3+, Zn2+ and Fe3+, did not reduce LRP protein levels in HBEC at non-toxic concentrations. We hypothesize that A[unreadable] clearance across the BBB is reduced in normal mice dosed with tracer levels of Cu due to Cu-induced decrease in LRP levels in cerebral endothelium, the BBB site in vivo, and that this effect is potentiated with normal aging. Four aims are proposed. Aim 1. The role of Cu on LRPmediated soluble A[unreadable] monomers clearance across the normal mouse BBB in vivo and effect of aging. Aim 2. The role of Cu on LRP-mediated soluble A[unreadable] oligomers clearance across the mouse BBB in vivo and effect of aging. Aim 3. The role of Cu on soluble A[unreadable] (monomers and oligomers) LRP binding and internalization in mouse brain capillaries. Aim 4. The role of Cu on LRP levels, synthesis and turnover in human brain endothelial cells. We will study clearance of A[unreadable]40 and A[unreadable]42 monomers and oligomers from the CNS in vivo and determine efflux at the BBB in control and Cu-dosed mice, at selected ages (4,9,15 and 24 months, after dosing), as well as in vitro using isolated brain capillaries. Mouse endogenous A[unreadable] levels in brain, cerebrospinal fluid (CSF) and plasma will be determined by ELISA. Cu levels in these samples and in brain microvessels will be determined by graphite furnace atomic absorption spectrophotometer. The effects of Cu on LRP levels, turnover and synthesis will be determined in brain endothelial cells. The proposed study will, for the first time, define Cu's role in the modulation of soluble A[unreadable] transport from brain, and provide new therapeutic insights on how to lower brain A[unreadable] by controlling its CNS barriers transport in Cu-potentiated neurodegenerative disorders. Project narrative: Accumulation of neurotoxic amyloid-[unreadable] (A[unreadable]) species in brain is accelerated in AD. A[unreadable] clearance by rapid transport across the blood-brain-barrier (BBB), requires LRP (low-density lipoprotein receptor-related protein1), the main receptor that clears A[unreadable] from brain. Copper (Cu) is associated with amyloid plaques in AD brains. It avidly binds A[unreadable] and may promote beta-sheet conformation, aggregation and toxicity. Our pilot data showed that mice, dosed with tracer levels of Cu in their drinking water, accumulates Cu in brain microvessels, and this effect is associated with down-regulation of LRP protein levels in these microvessels and increased A[unreadable] retention in brain. We are proposing a new role for Cu. We suggest that Cu down-regulates LRP in brain microvessels, and that this effect contributes to brain A[unreadable] accumulation. The proposed study will, for the first time, define Cu's role as an environmental factor in the modulation of soluble A[unreadable] transport from brain. These studies may provide new therapeutic insights on how to lower brain A[unreadable] by controlling its CNS barriers transport in Cu-potentiated neurodegenerative disorders.
Funding Period: ----------------2008 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Is RAGE still a therapeutic target for Alzheimer's disease?
    Richard J Deane
    Department of Neurosurgery, School of Arts and Sciences, University of Rochester, NY 14642, USA
    Future Med Chem 4:915-25. 2012
  2. pmc Low-density lipoprotein receptor-related protein 1: a physiological Aβ homeostatic mechanism with multiple therapeutic opportunities
    Abhay P Sagare
    Department of Physiology and Biophysics, and Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, 1501 San Pablo Street, Los Angeles, CA 90089, USA
    Pharmacol Ther 136:94-105. 2012
  3. pmc Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis
    Joseph M Castellano
    Department of Neurology, Hope Center for Neurological Disorders, Charles F and Joanne Knight Alzheimer s Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 109:15502-7. 2012
  4. pmc Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance
    Itender Singh
    Department of Neurosurgery, University of Rochester Medical Center, Rochester NY 14642, USA
    Proc Natl Acad Sci U S A 110:14771-6. 2013
  5. pmc Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease
    R Deane
    Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA
    CNS Neurol Disord Drug Targets 8:16-30. 2009
  6. pmc A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease
    Rashid Deane
    Center of Neurodegenerative and Vascular Brain Disorders, University of Rochester, Rochester, New York, USA
    J Clin Invest 122:1377-92. 2012

Scientific Experts

  • Rashid Deane
  • Abhay P Sagare
  • Itender Singh
  • Berislav V Zlokovic
  • Joseph M Castellano
  • R Tristan Kasper
  • Robert D Bell
  • Mireia Coma
  • Elaine Zhong
  • David Perlmutter
  • Robert Gelein
  • Joseph Ciszewski
  • Margaret Parisi
  • Tim West
  • Tristan R Kasper
  • Andrew C Paoletti
  • Andrew J Gottesdiener
  • David M Holtzman
  • Philip B Verghese
  • Ronald B DeMattos
  • Floy R Stewart

Detail Information

Publications6

  1. pmc Is RAGE still a therapeutic target for Alzheimer's disease?
    Richard J Deane
    Department of Neurosurgery, School of Arts and Sciences, University of Rochester, NY 14642, USA
    Future Med Chem 4:915-25. 2012
    ..Careful studies are needed in rodent and nonrodent animal models of AD with new the generation of RAGE antagonists to ensure safety and efficacy in chronic treatment before clinical trials...
  2. pmc Low-density lipoprotein receptor-related protein 1: a physiological Aβ homeostatic mechanism with multiple therapeutic opportunities
    Abhay P Sagare
    Department of Physiology and Biophysics, and Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, 1501 San Pablo Street, Los Angeles, CA 90089, USA
    Pharmacol Ther 136:94-105. 2012
    ....
  3. pmc Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis
    Joseph M Castellano
    Department of Neurology, Hope Center for Neurological Disorders, Charles F and Joanne Knight Alzheimer s Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 109:15502-7. 2012
    ..Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood Aβ clearance, which may serve as a useful therapeutic avenue in targeting Aβ clearance from the brain...
  4. pmc Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance
    Itender Singh
    Department of Neurosurgery, University of Rochester Medical Center, Rochester NY 14642, USA
    Proc Natl Acad Sci U S A 110:14771-6. 2013
    ..These findings should provide unique insights into preventative and/or therapeutic approaches to control neurotoxic Aβ levels in the aging brain. ..
  5. pmc Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease
    R Deane
    Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA
    CNS Neurol Disord Drug Targets 8:16-30. 2009
    ....
  6. pmc A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease
    Rashid Deane
    Center of Neurodegenerative and Vascular Brain Disorders, University of Rochester, Rochester, New York, USA
    J Clin Invest 122:1377-92. 2012
    ..Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD...