THE ROLE OF A-BETA SPECIES IN VASCULAR SMOOTH MUSCLE CELL AND CEREBRAL ARTERIOLE

Summary

Principal Investigator: Gregory J Zipfel
Abstract: DESCRIPTION (provided by applicant): The role of A[unreadable] species in vascular smooth muscle cell and cerebral arteriole dysfunction. Alzheimer's Disease (AD) is the leading cause of dementia;yet no therapy exists to slow or stop its progression. Recently, cerebrovascular (CV) pathology has been identified as a strong contributor to AD. Two key observations suggest that amyloid-[unreadable] peptide (A[unreadable]) may play a role by either causing or increasing the susceptibility to cerebral ischemia. First, cerebral blood flow (CBF) is reduced in early stages of AD, and the reactivity of cerebral blood vessels is impaired - both of which have been linked to the vasoactive properties of A[unreadable]. Second, most AD patients develop A[unreadable] deposits not only in brain but also in vessels - a condition known as cerebral amyloid angiopathy (CAA). CAA is a powerful risk factor for brain infarction and dementia, and is associated with severe CV dysfunction. A2 exists in several forms including soluble monomers (such as A[unreadable]40 and A[unreadable]42), soluble oligomers (toxic intermediate species), and insoluble fibrils (principle component of CAA). The former (primarily A[unreadable]40) and the latter (fibrillar A2 in the form of CAA) have been shown to powerfully alter CV function, while the vascular effects of A2 oligomers are not known. Our preliminary data suggest that the manner and extent to which monomeric A2 vs. fibrillar A2 cause CV dysfunction is different. We find that A[unreadable] monomers cause a hyper-contractile vascular phenotype that is due to endothelial cell (EC) and vascular smooth muscle cell (VSMC) dysfunction that is mediated via reactive oxygen species (ROS), while A[unreadable] fibrils in the form of CAA cause a hypo-contractile vascular phenotype that is primarily due to VSMC dysfunction that is mediated via ROS. We also identified a previously unrecognized contribution of ROS to CAA formation. The long-term objective of the proposed project is to test the central hypothesis that A[unreadable] species powerfully and adversely affect the cerebral circulation by inducing VSMC-mediated arteriole dysfunction via an ROS- mediated pathway. The specific aims are 1) to determine whether A[unreadable] species cause differential CV effects (hyper- vs. hypo-contractile impairment);2) to determine the ROS pathways by which A[unreadable] species cause VSMC and cerebral arteriole dysfunction;and 3) to determine the manner and extent to which ROS contribute to CAA formation, and to assess the functional benefits of reducing CAA via anti-ROS strategies. Methods used will include a) in vitro assessment of VSMC function after application of exogenous A[unreadable] species;b) in vivo assessment of cerebral arteriole function in transgenic mice producing endogenous A[unreadable] species;c) immunotherapy with anti-A[unreadable] antibodies that bind A[unreadable]40, A[unreadable]42, A[unreadable] oligomers, and/or A[unreadable] fibrils;d) pharmacologic and genetic inhibition of NADPH oxidase;d) pharmacologic and genetic inhibition of the A2-binding cell surface receptors, LRP1 and HSPGs;and e) quantitation of CAA, A[unreadable]40, A[unreadable]42, APP, and ApoE. If successful, these studies will result in an improved understanding of the mechanisms underlying A[unreadable]-induced CV deficits and CAA formation. This will likely facilitate development of therapies targeting A[unreadable] and its downstream effectors, which may ultimately improve the outcome of patients with AD, CAA, or both. PUBLIC HEALTH RELEVANCE: The role of A[unreadable]species in vascular smooth muscle cell and cerebral arteriole dysfunction. Alzheimer's Disease is the most common cause of dementia and the 6th leading cause of death in the United States;yet no effective treatment exists. Recently, stroke has been identified as a contributor to the memory problems of patients with Alzheimer's Disease. The goal of this project is to use cell culture and genetically engineered mice to improve our understanding of the factors that predispose Alzheimer's Disease patients to stroke. If successful, the results of the project may point to ways to develop effective treatments to prevent or reverse the memory problems of patients with Alzheimer's Disease in the future.
Funding Period: 2011-03-01 - 2016-01-31
more information: NIH RePORT

Top Publications

  1. pmc Resorufin analogs preferentially bind cerebrovascular amyloid: potential use as imaging ligands for cerebral amyloid angiopathy
    Byung Hee Han
    Department of Neurological Surgery, Washington University School of Medicine, St, Louis, MO 63110, USA
    Mol Neurodegener 6:86. 2011
  2. pmc Hypotension due to Kir6.1 gain-of-function in vascular smooth muscle
    Anlong Li
    Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO
    J Am Heart Assoc 2:e000365. 2013
  3. ncbi Preconditioning effect on cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage
    Young Woo Kim
    Department of Neurosurgery, Bucheon St Mary s Hospital, Catholic University of Korea, Bucheon, Republic of Korea Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri Neurovascular Service, Massachusetts General Hospital, Boston, Massachusetts Department of Radiology, UT Southwestern Medical Center, Dallas, Texas Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia Division of Neurological Surgery, Barrow Neurological Institute, St Joseph s Hospital and Medical Center, Phoenix, Arizona Department of Neurosurgery, University of Florida, Gainesville, Florida
    Neurosurgery 74:351-8; discussion 358-9. 2014

Research Grants

  1. HEALTHY AGING AND SENILE DEMENTIA
    John Morris; Fiscal Year: 2013
  2. Cerebrovascular Stress and Circulating Endothelial Cells
    Helena Parfenova; Fiscal Year: 2013
  3. CHRONIC INTERMITTENT HYPOXIA, NEUROVASCULAR DYSFUNCTION AND STROKE
    Costantino Iadecola; Fiscal Year: 2013
  4. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
  5. Flow Responsive Mediators of Inflammation and Survival
    Chen Yan; Fiscal Year: 2013
  6. Role of PPAR-gamma in Cerebral Endothelium
    Frank M Faraci; Fiscal Year: 2013
  7. Oxidative Stress and Vascular Smoth Muscle Cell Growth
    Bradford C Berk; Fiscal Year: 2013
  8. Behaviors on Surveys and in the Economy: HRS and Beyond
    Robert J Willis; Fiscal Year: 2013
  9. Massachusetts Alzheimer's Disease Research Center
    Bradley T Hyman; Fiscal Year: 2013
  10. Alzheimer's Disease Research Center
    Thomas J Montine; Fiscal Year: 2013

Detail Information

Publications3

  1. pmc Resorufin analogs preferentially bind cerebrovascular amyloid: potential use as imaging ligands for cerebral amyloid angiopathy
    Byung Hee Han
    Department of Neurological Surgery, Washington University School of Medicine, St, Louis, MO 63110, USA
    Mol Neurodegener 6:86. 2011
    ..Therefore, the development of a precise and specific non-invasive technique for diagnosing CAA in live patients is desired...
  2. pmc Hypotension due to Kir6.1 gain-of-function in vascular smooth muscle
    Anlong Li
    Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO
    J Am Heart Assoc 2:e000365. 2013
    ..1 causes Prinzmetal angina-like symptoms in mice. Conversely, overactivity of Kir6.2 induces neonatal diabetes in mice and humans, but consequences of Kir6.1 overactivity are unknown...
  3. ncbi Preconditioning effect on cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage
    Young Woo Kim
    Department of Neurosurgery, Bucheon St Mary s Hospital, Catholic University of Korea, Bucheon, Republic of Korea Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri Neurovascular Service, Massachusetts General Hospital, Boston, Massachusetts Department of Radiology, UT Southwestern Medical Center, Dallas, Texas Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia Division of Neurological Surgery, Barrow Neurological Institute, St Joseph s Hospital and Medical Center, Phoenix, Arizona Department of Neurosurgery, University of Florida, Gainesville, Florida
    Neurosurgery 74:351-8; discussion 358-9. 2014
    ..Recent experimental evidence indicates that endogenous mechanisms against cerebral vasospasm can be induced via preconditioning...

Research Grants30

  1. HEALTHY AGING AND SENILE DEMENTIA
    John Morris; Fiscal Year: 2013
    ..Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease. ..
  2. Cerebrovascular Stress and Circulating Endothelial Cells
    Helena Parfenova; Fiscal Year: 2013
    ....
  3. CHRONIC INTERMITTENT HYPOXIA, NEUROVASCULAR DYSFUNCTION AND STROKE
    Costantino Iadecola; Fiscal Year: 2013
    ..Ultimately, the results of the proposed studies may suggest novel mechanism-based approaches to prevent or treat the deleterious effects of this highly prevalent condition. ..
  4. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  5. Flow Responsive Mediators of Inflammation and Survival
    Chen Yan; Fiscal Year: 2013
    ..These studies should provide insight into mechanisms by which flow inhibits inflammation and facilitate development of therapeutic approaches to limit atherosclerosis. ..
  6. Role of PPAR-gamma in Cerebral Endothelium
    Frank M Faraci; Fiscal Year: 2013
    ....
  7. Oxidative Stress and Vascular Smoth Muscle Cell Growth
    Bradford C Berk; Fiscal Year: 2013
    ..Elucidating the tissue- and cell-specific pathways by which cyclophilin A modulates atherogenesis would provide insights for therapies to improve vascular function in this disease. ..
  8. Behaviors on Surveys and in the Economy: HRS and Beyond
    Robert J Willis; Fiscal Year: 2013
    ..abstract_text> ..
  9. Massachusetts Alzheimer's Disease Research Center
    Bradley T Hyman; Fiscal Year: 2013
    ..Going forward, the MADRC will continue to expand its clinical and neuropathological resources, its innovative training and scientific programs directed toward AD research. ..
  10. Alzheimer's Disease Research Center
    Thomas J Montine; Fiscal Year: 2013
    ..Montine;Project 2: Therapeutic Effects of Intra-Nasal Insulin Detemir, Dr. Suzanne Craft;Project 3: Modulation of A peptide accumulation and neuron damage in vivo with adult bone marrow transplants, Dr. C. Dirk Keene. ..
  11. Reperfusion and Neurovascular Injury in Stroke
    Pak H Chan; Fiscal Year: 2013
    ....
  12. APP/AB/Tau biochemistry in transgenic mice, familial and sporadic AD
    Alex E Roher; Fiscal Year: 2013
    ..A more complete understanding of AD molecular phenotypes and their clinical responses will aid in the discovery and application of efficacious treatments that will prevent AD or enhance the quality of life of AD patients. ..
  13. MOLECULAR AND CELLULAR MECHANISMS OF OSTEOPOROSIS
    Stavros C Manolagas; Fiscal Year: 2013
    ....