Cerebrovascular smooth muscle cell surface fibrillar A beta. Alteration of the proteolytic environment in the cerebral vessel wall.

[hereditary cerebral hemorrhage with amyloidosis]

Cerebrovascular deposition of the amyloid beta -protein (A beta ) 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 ). A beta 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 A beta 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 A beta 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 A beta fibrils serve as a site for tight binding of cell-secreted amyloid beta -precursor protein (A beta PP ). Since A beta PP is a potent inhibitor of key proteinases of coagulation cascade , its enhanced localization on the A beta fibrils would provide an strong anticoagulant environment . In addition , HCSM cell-surface A beta fibrils are potent stimulators of tissue plasminogen activator (tPA ) creating a profibrinolytic milieu . Our findings indicate that A beta 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 .