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

Abstract

Amyloid beta peptides (AbetaP) 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 AbetaPs 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 AbetaP(1-42), AbetaP(1-40), and AbetaP(25-35) on cultured endothelial cells. AbetaPs induced morphological changes that were observed within minutes after AbetaP treatment and led to eventual cellular degeneration. Cellular morphological changes were most sensitive to AbetaP(1-42). AbetaP(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-AbetaP antibody, AbetaP-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 AbetaP(1-42) induces rapid cellular degeneration by elevating intracellular calcium, most likely via calcium-permeable AbetaP 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 AbetaPs, may not have a direct causative role in AD pathogenic cascades.