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(The FASEB Journal. 2000;14:1244-1254.)
© 2000 FASEB

Fresh and nonfibrillar amyloid ß protein(1–40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AßP-channel-mediated cellular toxicity

YINWEN JUDY ZHU1,2, HAI LIN1 and RATNESHWAR LAL3

Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California 93106, USA

3Correspondence: Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106. E-mail: rlal{at}physics.ucsb.edu

Alzheimer’s disease (AD) is primarily nonfamilial or sporadic (SAD) in origin, although several genetic linkages are reported. Tissues from AD patients contain fibrillar plaques made of 39 to 43 amino acid-long amyloid beta peptide (AßP), although the mechanisms of AßP toxicity are poorly understood. AßP1–40 is the most prevalent AßP present in the neuronal and non-neuronal tissues from SAD patients. AßP1–40 toxicity has been examined mainly after prolonged incubation and correlates with the age and fibrillar morphology of AßP1–40. Globular and nonfibrillar AßPs are released continually during normal cellular metabolism; they elevate cellular Ca2+ and form cation-permeable channels. However, their role in cellular toxicity is poorly understood. We have used an integrated atomic force and light fluorescence microscopy (AFM-LFM), laser confocal microscopy, and calcium imaging to examine real-time and acute effect of fresh and globular AßP1–40 on cultured, aged human, AD-free fibroblasts. AFM images show that freshly prepared AßP1–40 in phosphate-buffered saline (PBS) are globular and do not form fiber for an extended time period. AßP1–40 induced rapid structural modifications, including cytoskeletal reorganization, retraction of cellular processes, and loss of cell–cell contacts, within minutes of incubation. This led to eventual cellular degeneration. AßP1–40-induced degeneration was prevented by anti-AßP antibody, zinc, and Tris, but not by tachykinin neuropeptides. In Ca2+-free extracellular medium, AßP1–40 did not induce cellular degeneration. In the presence of extracellular Ca2+, AßP1–40 induced a sustained increase in the cellular Ca2+. Thus, short-term and acute AßP1–40 toxicity is mediated by Ca2+ uptake, most likely via calcium-permeable AßP pores. Such rapid degeneration does not require fibrillar plaques, suggesting that the plaques may not have any causative role.—Zhu, Y. J., Lin, H., Lal, R. Fresh and nonfibrillar amyloid ß protein(1–40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AßP-channel-mediated cellular toxicity.


Key Words: atomic force microscope • scanning probe microscopy • amyloid beta protein • ion channels • Alzheimer’s disease




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