Alzheimer amyloid-beta is deposited in the neuropil and in brain blood vessels in transgenic Tg2576 mice that overexpress human amyloid-beta precursor protein (AbetaPP) containing the Swedish mutation (AbetaPP-Swe). Because the AbetaPP transgene in Tg2576 mice is placed behind the PrP promoter, all amyloid-beta, including vascular amyloid, is considered to be of neuronal origin. We studied the expression of the transgenic AbetaPP in smooth muscle cells cultured from brain blood vessels from Tg2576 mice. We found that brain vascular smooth muscle cells overexpressed human AbetaPP-Swe approximately 4 times the physiological levels of mouse AbetaPP. The cultured cells secreted abundant Abeta1-40 and Abeta1-42 and formed intracellular Abeta-immunoreactive granules. The percentage of cells containing intracellular Abeta and the amount of intracellular Abeta were significantly higher in cultures obtained from 14-month-old than from 4-month-old mice, as tested on first or second passages. During cell senescence in culture, intracellular accumulation of Abeta and C-terminal fragments of AbetaPP increased in cells derived from both 4- and 14-month-old mice. Vascular muscle cells from Tg2576 mice appear to be a valuable model of the intracellular accumulation of Abeta. We suggest that vascular muscle cells may be involved in the production of cerebrovascular amyloid in Tg2576 mice.