Abstract: Cerebrovascular deposition of the amyloid b-protein (Aβ) is a common pathologic event in patients with Alzheimer's disease (AD) and certain related disorders including hereditary cerebral hemorrhage with amyloidosis Dutch-type (HCHWA-D). Aβ deposition occurs primarily in the medial layer of the cerebral vessel wall in an assembled fibrillar state. These deposits are associated with several pathological responses including degeneration of the smooth muscle cells in the cerebral vessel wall. Severe cases of cerebrovascular Aβ deposition are also accompanied by loss of vessel wall integrity and hemorrhagic stroke. Although the reasons for this pathological consequence are unclear, altered proteolytic mechanisms within the cerebral vessel wall may be involved. Recent studies from our laboratory have shown that cell-surface assembly of Aβ into fibrillar structures causes cellular degeneration via an apoptotic pathway and creates an altered proteolytic microenvironment on the cell surface of human cerebrovascular smooth muscle cells (HCSM cells). For example, HCSM cell-surface Aβ fibrils serve as a site for tight binding of cell-secreted amyloid β-precursor protein (AβPP). Since AβPP is a potent inhibitor of key proteinases of coagulation cascade, its enhanced localization on the Aβ fibrils would provide an strong anticoagulant environment. In addition, HCSM cell-surface Aβ fibrils are potent stimulators of tissue plasminogen activator (tPA) creating a profibrinolytic milieu. Our findings indicate that Aβ fibril assembly on the HCSM cell surface causes cellular degeneration and results in both a strong anticoagulant and fibrinolytic environment. Together, these altered proteolytic events could create a setting that is conducive to loss of vessel wall integrity and hemorrhagic stroke.