Microvessels from Alzheimer's disease brains kill neurons in vitro

Understanding the pathogenesis of Alzheimer's disease is of widespread inte rest because it is an increasingly prevalent disorder that is progressive, fatal, and currently untreatable. The dementia of Alzheimer's disease is ca used by neuronal cell death, We demonstrate for the first time that blood v essels isolated from the brains of Alzheimer's disease patients can directl y kill neurons in vitro. Either direct co-culture of Alzheimer's disease mi crovessels with neurons or incubation of cultured neurons with conditioned medium from microvessels results in neuronal cell death, in contrast, vesse ls from elderly nondemented donors are significantly (P < 0.001) less letha l and brain vessels from younger donors are not neurotoxic. Neuronal killin g by either direct coculture with Alzheimer's disease microvessels or condi tioned medium is dose- and time-dependent. Neuronal death can occur by eith er apoptotic or necrotic mechanisms. The microvessel factor is neurospecifi c, killing primary cortical neurons, cerebellar granule neurons, and differ entiated PC-12 cells, but not non-neuronal cell types or undifferentiated P C-12 cells, Appearance of the neurotoxic factor is decreased by blocking mi crovessel protein synthesis with cycloheximide, The neurotoxic factor is so luble and likely a protein, because its activity is heat labile and trypsin sensitive. These findings implicate a novel mechanism of vascular-mediated neuronal cell death in Alzheimer's disease.