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Neuroscience Research Institute, University of California, Santa Barbara, California 93106, USA
1Correspondence: Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA. E-mail: bhatia{at}lifesci.ucsb.edu
Amyloid ß peptides (AßP) 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 AßPs 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 AßP1–42, AßP1–40, and AßP25–35 on cultured endothelial cells. AßPs induced morphological changes that were observed within minutes after AßP treatment and led to eventual cellular degeneration. Cellular morphological changes were most sensitive to AßP1–42. AßP1–42-induced morphological changes were observed at nanomolar concentrations and were accompanied by an elevated cellular calcium level. Morphological changes were prevented by anti-AßP antibody, AßP-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 AßP1–42 induces rapid cellular degeneration by elevating intracellular calcium, most likely via calcium-permeable AßP 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 AßPs, may not have a direct causative role in AD pathogenic cascades.—Bhatia, R., Lin H., Lal, R. Fresh and globular amyloid ß protein (1–42) induces rapid cellular degeneration: evidence for AßP channel-mediated cellular toxicity
Key Words: AFM • scanning probe microscopy • real-time cellular imaging • endothelial cells • amyloid ß protein • neurotoxicity • Alzheimer’s disease • calcium imaging • cytoskeletal reorganization
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