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Extracellular amyloid beta 42 causes necrosis, inhibition of nuclear division, and mitotic disruption under both folate deficient and folate replete conditions as measured by the cytokinesis‐block micronucleus cytome assay
Author(s) -
Lee Sau Lai,
Thomas Philip,
Fenech Michael
Publication year - 2014
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.21811
Subject(s) - micronucleus , micronucleus test , extracellular , cytokinesis , biology , binucleated cells , dna damage , necrosis , apoptosis , microbiology and biotechnology , medicine , biochemistry , cell division , cell , toxicity , dna , genetics
Alzheimer's disease is associated with accumulation of extracellular beta amyloid peptide 42 (Aβ42) which may induce DNA damage and reduce cellular regenerative potential. These effects may be exacerbated under conditions of folate deficiency. The aim of this study was to investigate whether extracellular Aβ42 induces DNA damage and cell death in human peripheral lymphocytes and whether there is an interactive effect between extracellular Aβ42 and folic acid status. Peripheral blood lymphocytes were cultured in medium under conditions of both low and high folate (20 and 200 nM, respectively) and challenged with either Aβ42 or the physiologically normal form Aβ40 (both at 5, 10, 15 µM). Genome stability and cytotoxicity events were investigated using the cytokinesis‐block micronucleus cytome (CBMN‐cyt) assay. Outcome measures scored included the nuclear division index (NDI), necrosis, apoptosis, binucleated cells with micronuclei (MN), nucleoplasmic bridges (NPB), and nuclear buds (NBUD) and abnormally shaped nuclei (circular, (CIR) and horse‐shoe, (HS) that may be indicative of mitotic disruption. Folic acid deficiency significantly reduced NDI ( P < 0.001) and increased all the DNA damage biomarkers (MN, NPB, NBUD, HS, CIR), ( P < 0.001). In contrast, exposure to Aβ40 had no impact on CBMN cytome biomarkers but Aβ42 significantly reduced NDI ( P < 0.01), increased necrosis ( P < 0.05) and frequency of cells with circular nuclei ( P < 0.01). There was no evidence of an interaction between Aβ42 and folic acid with respect to CBMN cytome biomarkers. Extracellular Aβ42 appears to have cytotoxic and cytostatic effects but its effect on chromosomal instability appears to be small relative to folate deficiency. Environ. Mol. Mutagen. 55:1–14, 2014. © 2013 Wiley Periodicals, Inc.