The progression of Alzheimer's disease and related disorders involves amyloid beta-protein (A beta) deposition and pathologic changes in the parenchyma as well as cerebral blood vessels. The cerebrovascular A beta deposits in these disorders are associated with degenerating smooth muscle cells in the vessel wall, which have been shown to express the A beta precursor (A beta PP) and A beta. Here, we show that A beta 1-42, an abundant cerebrovascular form of A beta, causes cellular degeneration in cultured human cerebrovascular smooth muscle cells. This stress response is accompanied by a striking increase in the levels of cellular A beta PP and soluble A beta peptide produced in these degenerating cells. These data provide the first experimental evidence that A beta can potentially contribute to the onset and progression of the cerebrovascular pathology. The present findings suggest that this mechanism may involve a molecular cascade with a novel product-precursor relationship that results in the adverse production and subsequent accumulation of A beta.