Abstract
Amyloid beta (Abeta), a peptide family produced and deposited in neurons and endothelial cells (EC), is found at subnanomolar concentrations in the plasma of healthy individuals. Simple conformational changes produce a form of Abeta, Abeta42, which creates toxic plaque in the brains of Alzheimer's patients. Oxidative stress induced blood brain barrier degeneration has been proposed as a key factor for Abeta42 toxicity, but cannot account for lack of injury from the same peptide in healthy tissues. We hypothesized that cell state mediates Abeta effect. Thus, we examined the viability of aortic EC, vascular smooth muscle cells (SMC) and epithelial cells (EPI) in different states in the presence of Abeta secreted from transfected Chinese hamster ovary cells (CHO). Abeta was more toxic to all cell types when they were subconfluent. Subconfluent EC sprouted and SMC and EPI were inhibited by Abeta. Confluent EC were virtually resistant to Abeta and suppressed Abeta production by Abeta+CHO. Products of subconfluent EC overcame this resistant state, stimulating the production and toxicity of Abeta42. Confluent EC overgrew approximately 35% beyond their quiescent state in the presence of Abeta conditioned in media from subconfluent EC. These findings imply that Abeta42 may well be even more cytotoxic to cells in injured or growth states and potentially explain the variable and potent effects of this protein. One may now need to consider tissue and cell state in addition to local concentration of and exposure duration to Abeta. The specific interactions of Abeta and EC in a state-dependent fashion may help understand further the common and divergent forms of vascular and cerebral toxicity of Abeta and the spectrum of AD.