ROLES OF VASCULAR AMYLOID BETA PROTEIN PRECURSOR

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The objectives of the proposed studies are two-fold and reflect research areas in the biochemistry, functional properties, and cell biology of PN- 2/AbetaPP that are currently funded by two research grants. First, the biochemical interactions between PN-2/AbetaPP and coagulation factors will be investigated. Specifically, the present proposal will focus on studies concerning interactions between coagulation factor X1a and PN-2/AbetaPP and the effects of high molecular weight kininogen and the effects of biologic surfaces on these interactions. In addition, characterization of the protease inhibitory and potential anticoagulant properties of a recombinant Kunitz-type protease inhibitor domain of a related AbetaPP- homolog are planned to better understand the functional relatedness of this homolog protein to PN2/AbetaPP. Second, in a somewhat different, but related and important series of studies, PN-2/AbetaPP expression and processing in cerebral blood vessels from postmortem human brain tissue and in cultured cerebrovascular smooth muscle cells will be investigated. These series of investigations will begin to elucidate how PN-2/AbetaPP may normally serve as an anticoagulant in the cerebrovasculature and how it may abnormally be involved with intracerebral hemorrhaging in patients with a rare disorder that is related to Alzheimer's disease known as hereditary cerebral hemorrhage with amyloidosis-Dutch type. Better understanding of the biochemistry and cerebrovascular cell biology of PN- 2/AbetaPP will provide insight into its normal function as well as the patho-biochemistry and pathophysiology of this protein in certain disease states.