The overall hypothesis of this proposal is that the human cerebrovascular smooth muscle (HCSM) cell surface promotes the assembly of pathogenic forms of amyloid B-protein (AB) into fibrils and that an interaction between secreted amyloid B-protein precursor (sABPP) and HCSM cell surface fibrillar AB contributes to the downstream pathologic changes that occur in cerebral blood vessels of patients with Alzheimer' s disease (AD) and related disorders including hereditary cerebral hemorrhage with amyloidosis Dutch-type (HCHWA-D). Our overall reseach efforts have focused on elucidating the cellular mechanisms that underlie the cerebrovascular pathology of AD, HCHWA-D, and related disorders. The objectives of the present proposal are to investigate the interaction between fibrillar forms of AB and sABPP that occur on the HCSM cell surface that induces several key pathologic responses in these cells. To accomplish this we propose five specific aims. First, we plan to identify specific factors on HCSM cells that promote pathogenic A13 fibril formation. Second, we wifi determine the specific domain on ABPP that mediates its binding to fibrillar forms of AB. Third, we wifi investigate if altering the level of AI3PP expression affects the ability of pathogenic forms of AB to induce pathologic responses in HCSM cells. Fourth, we will determine the specific domain on sAJ3PP that is involved with inducing downstream pathologic responses in cultured HCSM cells. Last, we will begin to identify pathologic signaling pathways that are activated in response to the fibrillar AB-sABPP interaction. These combined investigations intend to utilize cultured HCSM cells as an in vitro paradigm to characterize the consequences of the interaction between fibrillar AB and sABPP that occurs on the cell surface that potentially leads to the downstream cerebrovascular pathologic changes observed in patients with AD and related disorders. Certain aspects of this pathologic cascade may be specific for HCSM and related cells in the cerebral blood vessel wall and, therefore, may help to explain the different etiologies between the parenchymal and cerebrovascular AB induced pathologies in AD and related disorders. Finally, the pathologic interactions that occur between fibrillar AB and sABPP on the surfaces of HCSM cells may have potential therapeutic implications. Characterization of the molecules and domains involved in these interactions and detennining the consequences of these interactions with respect to inducing key pathologic responses may provide an opportunity for the future development of novel intervention strategies to ameliorate the cerebrovascular pathology of AD, HCHWA-D, and related disorders.
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