Fresh and globular amyloid β protein (1-42) induces rapid cellular degeneration:: evidence for AβP channel-mediated cellular toxicity

Amyloid beta peptides (A beta P) deposit as plaques in vascular and parenchymal areas of Alzheimer's disease (AD) tissues and Down's syndrome patients. Although neuronal toxicity is a feature of late stages of AD, vascular pathology appears to be a feature of all stages of AD. Globular and nonfibrillar A beta Ps are continuously released during normal cellular metabolism, form calcium-permeable channels, and alter cellular calcium level. We used atomic force microscopy, laser confocal microscopy, and calcium imaging to examine the real-time and acute effects of fresh and globular A beta P1-42, A beta P1-40, and A beta P25-35 on cultured endothelial cells. A beta Ps induced morphological changes that were observed within minutes after A beta P treatment and led to eventual cellular degeneration. Cellular morphological changes were most sensitive to A beta P1-42. APP(1-42)-induced morphological changes were observed at nanomolar concentrations and were accompanied by an elevated cellular calcium level. Morphological changes were prevented by anti-A beta P antibody, A beta P-channel antagonist zinc, and the removal of extracellular calcium, but not by tachykinin neuropeptide, voltage-sensitive calcium channel blocker cadmium, or antioxidants DTT and Trolox. Thus, nanomolar fresh and globular A beta P1-42 induces rapid cellular degeneration by elevating intracellular calcium, most likely via calcium-permeable A beta P channels and not by its interaction with membrane receptors or by activating oxidative pathways. Such rapid degeneration also suggests that the plaques, and especially fibrillar A beta Ps, may not have a direct causative role in AD pathogenic cascades.-Bhatia, R., Lin H., Lal, R. Fresh and globular amyloid beta protein (1-42) induces rapid cellular degeneration: evidence for APE channel-mediated cellular toxicity.