The overall hypothesis that forms the basis of this proposal is that an interaction between the amyloid beta-protein (Abeta) and the amyloid beta-protein precursor (AbetaPP), and the cell surface in human cerebrovascular smooth muscle (HCSM) cells is involved in the initiation and progression of the cerebrovascular smooth muscle cellular pathology of Alzheimer's disease (AD) and related disorders including hereditary cerebral hemorrhage with amyloidosis Dutch-type (HCHWA-D). The applicants' overall research efforts have focused on elucidating the cellular mechanism that underlie the cerebrovascular pathology of AD, HCHWA-D and related disorders. The objectives of the present proposal are to investigate a recently identified interaction between certain forms of Abeta and cellular AbetaPP in cultured HCSM cells that induce several key pathologic responses in these cells. This mechanism may be specific for HSCM and related cells in the cerebral blood vessel wall and, therefore, may help to explain the different etiologies between the parenchymal and cerebrovascular Abeta induced pathologies in AD and relates disorder. They plan to identify the precise domain on AbetaPP where Abeta binds to induce the pathologic responses in HCSM cells. Investigations will be conducted to determine if AbetaPP is implicated in cell-surface Abeta fibril formation and if these fibrils are involved with promoting the pathological responses in HCSM cells. Lastly, they will determine if altering the endogenous level of AbetaPP expression affects the ability of Abeta to induce pathologic responses in HCSM cells. These combined investigations intend to utilize cultured HCSM cells as an in vitro paradigm to identify the Abeta binding site on AbetaPP and characterize the consequences of this interaction on the cells surface that potentially leads to the initiation and progression of the cerebrovascular smooth muscle cellular pathology of AD, HCHWA-D and related disorders. Although early in its discovery, the pathologic interaction between Abeta and AbetaPP in HCSM cells have potential therapeutic implications. Identification of the precise Abeta binding site on AbetaPP and determining the nature of the interactions that are involved with inducing the key pathologic responses may provide an opportunity for the future development of novel intervention strategies to block the initiation and/or halt the further progression of the cerebrovascular pathology of AD, HCHWA-D, and related disorders.
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