Amyloid Beta Protein Precursor Influences Cerebral Thrombosis

Summary

Principal Investigator: William Van Nostrand
Abstract: Secreted Kunitz proteinase inhibitor (KPI) domain-containing forms of the amyloid beta-protein precursor (ABetaPP) are also known as the previously described cell secreted proteinase inhibitor designated protease nexin-2 (PN2). Extensive earlier work from our laboratory has shown that PN2/ABetaPP is a potent inhibitor of several key pro-thrombotic enzymes and can inhibit thrombosis in vitro. These defining biochemical features of PN2/ABetaPP, coupled with its abundance in brain and in circulating blood platelets, have suggested a role for this protein in regulating thrombosis during episodes of cerebral vascular injury. Hemorrhagic and ischemic strokes are major health issues that can lead to severe debilitation and morbidity. Both hemorrhagic and ischemic strokes involve alteration of pro-thrombotic pathways. A precise understanding of the molecules and mechanisms involved in regulating cerebral thrombosis during these deleterious vascular events remains unresolved. The goal of this study is to define the role of the proteinase inhibitory properties of the ABetaPP in regulating cerebral thrombosis during cerebral vascular injury. In this regard, the overall hypothesis that forms the basis for this proposal is that the proteinase inhibitory function of PN2/ABetaPP plays a significant role in regulating cerebral thrombosis during cerebral vascular injury. The three specific aims of this proposal are as follows. First, determine if specific over-expression of platelet PN2/ABetaPP in transgenic mice will decrease thrombus formation, brain lesion, and behavioral deficits associated with cerebral vascular injury. Second, determine if specific over- expression of PN2/ABetaPP in brain in transgenic mice will modulate cerebral thrombosis in models of intracerebral hemorrhage and transient focal ischemia. Third, determine if deletion of the proteinase inhibitory activity of PN2/ABetaPP, amyloid precursor-like protein 2 (APLP2), or both will increase thrombus formation, brain lesion, and behavioral deficits in models of cerebral vascular injury. Together, these proposed translational investigations, which stem from our extensive previous in vitro work on the proteinase inhibitory properties of PN2/ABetaPP, will provide new insight into important physiological functions of this protein that currently remain unknown. This may lead to new avenues for developing strategies to regulate cerebral thrombosis and limit damage to the brain as a consequence of hemorrhagic and ischemic stroke.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Increased severity of hemorrhage in transgenic mice expressing cerebral protease nexin-2/amyloid beta-protein precursor
    Feng Xu
    Stroke 38:2598-601. 2007
  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. pmc AbetaPP/APLP2 family of Kunitz serine proteinase inhibitors regulate cerebral thrombosis
    Feng Xu
    Department of Medicine, Stony Brook University, Stony Brook, New York 11794 8153, USA
    J Neurosci 29:5666-70. 2009
  4. pmc Clearance of amyloid-β protein deposits in transgenic mice following focal cerebral ischemia
    W E Van Nostrand
    Department of Neurosurgery and Medicine, Stony Brook University, Stony Brook, NY 11794 8122, USA
    Neurodegener Dis 10:108-11. 2012

Scientific Experts

  • Feng Xu
  • William E Van Nostrand
  • Mary Lou Previti
  • W E Van Nostrand
  • Judianne Davis
  • F Xu
  • J Davis
  • M L Previti
  • Alvin H Schmaier
  • Marvin T Nieman
  • Michael P Vitek
  • Nastaran Gharkholonarehe
  • Carol A Colton

Detail Information

Publications4

  1. 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...
  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. pmc AbetaPP/APLP2 family of Kunitz serine proteinase inhibitors regulate cerebral thrombosis
    Feng Xu
    Department of Medicine, Stony Brook University, Stony Brook, New York 11794 8153, USA
    J Neurosci 29:5666-70. 2009
    ..Together, these results indicate that AbetaPP and APLP2 share overlapping anticoagulant functions with regard to regulating thrombosis after cerebral vascular injury...
  4. pmc Clearance of amyloid-β protein deposits in transgenic mice following focal cerebral ischemia
    W E Van Nostrand
    Department of Neurosurgery and Medicine, Stony Brook University, Stony Brook, NY 11794 8122, USA
    Neurodegener Dis 10:108-11. 2012
    ..On the other hand, it remains unclear how cerebral ischemia affects preexisting Aβ deposits in the brain. Here we determine the consequences of focal ischemic stroke on existing Aβ pathology in Tg-SwDI transgenic mice...