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Fresh and nonfibrillar amyloid β protein(1–40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AβP‐channel‐mediated cellular toxicity
Author(s) -
Zhu Yinwen Judy,
Lin Hai,
Lal Ratneshwar
Publication year - 2000
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.14.9.1244
Subject(s) - extracellular , toxicity , amyloid (mycology) , confocal microscopy , microbiology and biotechnology , biophysics , chemistry , extracellular matrix , biology , biochemistry , inorganic chemistry , organic chemistry
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 (AβP), although the mechanisms of AβP toxicity are poorly understood. AβP 1–40 is the most prevalent AβP present in the neuronal and non‐neuronal tissues from SAD patients. AβP 1–40 toxicity has been examined mainly after prolonged incubation and correlates with the age and fibrillar morphology of AβP 1–40 . Globular and nonfibrillar AβPs are released continually during normal cellular metabolism; they elevate cellular Ca 2+ 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 AβP 1–40 on cultured, aged human, AD‐free fibroblasts. AFM images show that freshly prepared AβP 1–40 in phosphate‐buffered saline (PBS) are globular and do not form fiber for an extended time period. AβP 1–40 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. AβP 1–40 ‐induced degeneration was prevented by anti‐AβP antibody, zinc, and Tris, but not by tachykinin neuropeptides. In Ca 2+ ‐free extracellular medium, AβP 1–40 did not induce cellular degeneration. In the presence of extracellular Ca 2+ , AβP 1–40 induced a sustained increase in the cellular Ca 2+ . Thus, short‐term and acute AβP 1–40 toxicity is mediated by Ca 2+ uptake, most likely via calcium‐permeable AβP 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 β protein(1–40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AβP‐channel‐mediated cellular toxicity. FASEB J . 14, 1244–1254 (2000)