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  • Title: Disruption of pathologic amyloid beta-protein fibril assembly on the surface of cultured human cerebrovascular smooth muscle cells.
    Author: Van Nostrand WE, Melchor JP.
    Journal: Amyloid; 2001 Jul; 8 Suppl 1():20-7. PubMed ID: 11676286.
    Abstract:
    Cerebral amyloid beta-protein (Abeta) angiopathy (CAA) is a common pathological feature of Alzheimer's disease and several related disorders. In this condition, the accumulation offibrillar Abeta deposits is associated with degeneration of smooth muscle cells within the cerebral blood vessel wall. We have been using primary cultures of human cerebrovascular smooth muscle (HCSM) cells to investigate pathogenic mechanisms of Abeta in CAA. The specific assembly of Abeta fibrils on the surface of these cell types initiates several pathologic responses including increased expression and cell surface accumulation of the Abeta precursor protein (AbetaPP) and induction of apoptotic cell death. These pathologic responses are not observed with preparations of Abeta that are assembled into fibrils in solution, further underscoring the significance of the fibril assembly process on the cell surface. Since cell surface Abeta fibril assembly is the key initiator of the cerebrovascular cellular pathology that is observed in vitro, inhibition of this process remains an attractive therapeutic target for CAA. We have tested the efficacy of a variety of compounds that have been reported to inhibit Abeta fibril assembly in solution and block the neurotoxic properties of Abeta in vitro. The vast majority of these agents were ineffective in inhibiting the cell surface fibrillar assembly of Abeta and the subsequent pathologic responses in the cultured HCSM cells. This emphasizes the likely requirement of therapeutic compounds that are effective in disrupting cell surface-driven Abeta fibril assembly in the treatment of CAA.
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