Transgenic Model for Cerebral Amyloid Angiopathy

Summary

Principal Investigator: William Van Nostrand
Abstract: [unreadable] DESCRIPTION (provided by applicant): Cerebrovascular deposition of the amyloid [unreadable]-protein (A[unreadable]), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease (AD) and several related hereditary cerebral hemorrhage with amyloidosis (HCHWA) disorders. A[unreadable] is proteolytically derived from its parent molecule the amyloid [unreadable]-protein precursor (A[unreadable]PP). Apolipoprotein E (ApoE) genotype can facilitate both cerebrovascular A[unreadable] deposition and hemorrhagic stroke. It is significant that CAA accounts for up to 20% of cases of spontaneous primary intracerebral hemorrhage. Moreover, CAA is most severe in HCHWA patients often resulting in early recurrent and fatal intracerebral hemorrhages. The reason as to why there is preferential cerebrovascular A[unreadable] deposition in HCHWA disorders leading to hemorrhagic stroke and how ApoE may facilitate these pathological processes remains unresolved. [unreadable] [unreadable] We have shown that certain HCHWA mutant forms of A[unreadable], which exhibit a loss or change in charge at peptide residues 22 or 23, possess enhanced pathogenic properties towards cultured cerebrovascular cells. In addition, ApoE genotype can further influence the pathogenic effects of A[unreadable] in these in vitro paradigms. However, many of these issues can be better studied in valid in vivo models for CAA. Therefore, the overall hypotheses that forms the basis of this proposal is that expression of HCHWA mutant A[unreadable]PP in transgenic mice will lead to the preferential development of CAA and human ApoE genotype can further influence this pathology and promote cerebral hemorrhage. The broad objectives of this proposal are two-fold. First, we will compare the pathological consequences of neuronal over-expression of several human A[unreadable]PP forms yielding either wild-type or CAA mutant A[unreadable] with regards to the development of CAA. The CAA mutant forms A[unreadable]PP will contain either a single Dutch E22Q AB substitution or double Dutch/Iowa E22Q,D23N A[unreadable] substitutions. Second, the influence of human ApoE genotype on A[unreadable] deposition, the development of CAA, and cerebral hemorrhage will be investigated in these in vivo models. These proposed studies stem from our overall focus and continuing work on investigating the role of ABPP and its derived fragment A6 in the development of CAA, loss of vessel wall integrity, and hemorrhagic stroke. Completion of these specific aims will produce valuable models for both the further study of pathogenic mechanisms in CAA and in vivo systems to develop and test therapeutic strategies to mitigate cerebrovascular A[unreadable] deposition and the subsequent pathological consequence of hemorrhagic stroke. [unreadable] [unreadable]
Funding Period: 1998-05-01 - 2008-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Human apolipoprotein E2 promotes parenchymal amyloid deposition and neuronal loss in vasculotropic mutant amyloid-β protein Tg-SwDI mice
    Feng Xu
    Department of Neurosurgery and Medicine, Stony Brook University, Stony Brook, NY 11794 8122, USA
    J Alzheimers Dis 31:359-69. 2012
  2. pmc Human apolipoprotein E redistributes fibrillar amyloid deposition in Tg-SwDI mice
    Feng Xu
    Department of Medicine, Stony Brook University, Stony Brook, New York 11794 8153, USA
    J Neurosci 28:5312-20. 2008
  3. ncbi Experimental investigation of antibody-mediated clearance mechanisms of amyloid-beta in CNS of Tg-SwDI transgenic mice
    Vitaly Vasilevko
    The Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California 92697 4540, USA
    J Neurosci 27:13376-83. 2007
  4. pmc Induction of complement proteins in a mouse model for cerebral microvascular A beta deposition
    Rong Fan
    Department of Medicine, Stony Brook University, Stony Brook, NY 11794 USA
    J Neuroinflammation 4:22. 2007
  5. ncbi Increased severity of hemorrhage in transgenic mice expressing cerebral protease nexin-2/amyloid beta-protein precursor
    Feng Xu
    Stroke 38:2598-601. 2007
  6. ncbi Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid
    Rong Fan
    Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA
    J Neurosci 27:3057-63. 2007
  7. pmc Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid beta-protein precursor transgenic mice
    F Xu
    Department of Medicine, Health Sciences Center T 15 083, Stony Brook University, Stony Brook, NY 11794 8153, USA
    Neuroscience 146:98-107. 2007
  8. ncbi Metallothionein-I and -III expression in animal models of Alzheimer disease
    J Carrasco
    Institute of Neurosciences, Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Sciences, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain 08193
    Neuroscience 143:911-22. 2006
  9. ncbi Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models
    Martin C Herzig
    Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tubingen, Germany
    Brain Pathol 16:40-54. 2006
  10. pmc Protease nexin-2/amyloid beta-protein precursor limits cerebral thrombosis
    Feng Xu
    Department of Medicine, Stony Brook University, NY 11794, USA
    Proc Natl Acad Sci U S A 102:18135-40. 2005

Scientific Experts

  • William Van Nostrand
  • Martin C Herzig
  • Feng Xu
  • Mary Lou Previti
  • Judianne Davis
  • Jianting Miao
  • Rong Fan
  • Michael P Vitek
  • F Xu
  • Carol A Colton
  • Vitaly Vasilevko
  • J Carrasco
  • Galina Romanov
  • Kelly Ziegler
  • Veronica Hirsch-Reinshagen
  • Nastaran Gharkholonarehe
  • J Davis
  • Kelly DeFilippis
  • M Vasek
  • A M Grande
  • J K Robinson
  • David H Cribbs
  • John K Robinson
  • Alicia M Grande
  • M L Previti
  • J Hidalgo
  • M Penkowa
  • P Adlard
  • C Cotman
  • A Quintana
  • Marcel M Verbeek
  • Gavin H Tansley
  • Michael R Hayden
  • Irene Otte-Holler
  • Luis F Maia
  • Cheryl L Wellington
  • Judes Poirier
  • Sean A McIsaac
  • Jennifer Y Chan
  • Pamela F Parkinson
  • Jean Francois Blain
  • Kathryn E Naus
  • Braydon L Burgess

Detail Information

Publications14

  1. ncbi Human apolipoprotein E2 promotes parenchymal amyloid deposition and neuronal loss in vasculotropic mutant amyloid-β protein Tg-SwDI mice
    Feng Xu
    Department of Neurosurgery and Medicine, Stony Brook University, Stony Brook, NY 11794 8122, USA
    J Alzheimers Dis 31:359-69. 2012
    ..These findings suggest that compared with human ApoE4, human ApoE2 does not beneficially influence the quantitative or spatial accumulation of human Dutch/Iowa CAA mutant amyloid or associated pathology in transgenic mice...
  2. pmc Human apolipoprotein E redistributes fibrillar amyloid deposition in Tg-SwDI mice
    Feng Xu
    Department of Medicine, Stony Brook University, Stony Brook, New York 11794 8153, USA
    J Neurosci 28:5312-20. 2008
    ....
  3. ncbi Experimental investigation of antibody-mediated clearance mechanisms of amyloid-beta in CNS of Tg-SwDI transgenic mice
    Vitaly Vasilevko
    The Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California 92697 4540, USA
    J Neurosci 27:13376-83. 2007
    ..Thus, approaches that deliver immunotherapy to the brain may be more effective at clearing Abeta than immunization strategies in which the majority of the antibodies are in the periphery...
  4. pmc Induction of complement proteins in a mouse model for cerebral microvascular A beta deposition
    Rong Fan
    Department of Medicine, Stony Brook University, Stony Brook, NY 11794 USA
    J Neuroinflammation 4:22. 2007
    ..Our findings demonstrate that Tg-SwDI mice exhibit elevated complement protein expression in response to fibrillar vascular A beta deposition that is observed in patients with familial CAA...
  5. ncbi Increased severity of hemorrhage in transgenic mice expressing cerebral protease nexin-2/amyloid beta-protein precursor
    Feng Xu
    Stroke 38:2598-601. 2007
    ..Although little is known of its physiological function, the potent inhibition of certain prothrombotic proteinases by PN2/AbetaPP suggests that it may function to regulate cerebral thrombosis during vascular injury events...
  6. ncbi Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid
    Rong Fan
    Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA
    J Neurosci 27:3057-63. 2007
    ..These finding suggest that anti-inflammatory treatment targeted for cerebral microvascular amyloid-induced microglial activation can improve cognitive deficits without altering the accumulation and distribution of Abeta...
  7. pmc Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid beta-protein precursor transgenic mice
    F Xu
    Department of Medicine, Health Sciences Center T 15 083, Stony Brook University, Stony Brook, NY 11794 8153, USA
    Neuroscience 146:98-107. 2007
    ..These findings indicate that early-onset accumulation of subicular microvascular amyloid and accompanying neuroinflammation correlates with impaired performance in the learning and memory task in Tg-SwDI mice...
  8. ncbi Metallothionein-I and -III expression in animal models of Alzheimer disease
    J Carrasco
    Institute of Neurosciences, Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Sciences, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain 08193
    Neuroscience 143:911-22. 2006
    ..In contrast to MT-I, MT-III mRNA expression was not significantly altered in any of the models examined suggesting that the various MT isoforms may have different roles in these experimental systems, and perhaps also in human AD...
  9. ncbi Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models
    Martin C Herzig
    Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tubingen, Germany
    Brain Pathol 16:40-54. 2006
    ....
  10. pmc Protease nexin-2/amyloid beta-protein precursor limits cerebral thrombosis
    Feng Xu
    Department of Medicine, Stony Brook University, NY 11794, USA
    Proc Natl Acad Sci U S A 102:18135-40. 2005
    ..These findings indicate that PN2/AbetaPP plays a significant role in regulating cerebral thrombosis and that modest increases in this protein can profoundly enhance cerebral hemorrhage...
  11. ncbi The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease
    Veronica Hirsch-Reinshagen
    Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V4Z 5H5, Canada
    J Biol Chem 280:43243-56. 2005
    ..These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo...
  12. ncbi Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double A beta in human A betaPP transgenic mice
    Judianne Davis
    Department of Medicine, Health Sciences Center, Stony Brook University, HSC T 15 083, Stony Brook, NY 11794 8153, USA
    Neurobiol Aging 27:946-54. 2006
    ....
  13. pmc Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein
    Jianting Miao
    Department of Medicine, HSC, Stony Brook University, Stony Brook, NY 11794 8153, USA
    Am J Pathol 167:505-15. 2005
    ..Together, these studies identify the Tg-SwDI mouse as a unique model to investigate selective accumulation of cerebral microvascular amyloid and the associated neuroinflammation...
  14. ncbi Reducing cerebral microvascular amyloid-beta protein deposition diminishes regional neuroinflammation in vasculotropic mutant amyloid precursor protein transgenic mice
    Jianting Miao
    Department of Medicine, Stony Brook University, Stony Brook, New York 11794 8153, USA
    J Neurosci 25:6271-7. 2005
    ....