title: Advanced glycation endproduct precursor alters intracellular amyloid-beta/A beta PP carboxy-terminal fragment aggregation and cytotoxicity.
abstract: Carbonyl stress from products of lipid peroxidation, such as 4-hydroxynonenal (HNE), and products of sugars in diabetes mellitus, such as methylglyoxal (MG) and glyoxal (G), may contribute to neurodegeneration in Alzheimer's disease (AD). We tested the hypothesis that these carbonyls alter the proposed central pathogenic mechanism of AD, intracellular amyloid-beta (A beta)-mediated cytotoxicity, using a human neuroblastoma cell line that conditionally expresses carboxy-terminal fragments (CTFs) of the amyloid precursor protein. HNE was a potent cytotoxin, whereas G was mildly cytotoxic; cytotoxicity from each was independent of A beta/CTF expression and not altered by alpha-tocopherol. In contrast, MG cytotoxicity was enhanced by the induced expression of A beta/CTFs and suppressed by alpha-tocopherol. alpha-tocopherol cytoprotection was accompanied by decreased A beta/CTF aggregation. G also promoted beta/CTF aggregation but by mechanisms unaffected by alpha-tocopherol treatment. Our findings showed that A beta/CTF aggregation and cytotoxicity may be profoundly altered by aldehydes associated with diabetes and that in the case of MG, this process is suppressed by alpha-tocopherol. Moreover, our results suggest that while intracellular aggregation of A beta/CTFs may be necessary for the development of toxicity attributable to their expression in this model, the presence of high-molecular weight aggregated A beta/CTFs does not invariably lead to cytotoxicity.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98104, USA. rwoltjer@u.washington.edu
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.forename: Joyce J
authors.initials: JJ
authors.lastname: Ou
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000276:immunology; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D003603:Cytotoxins / Q000378:metabolism; D048909:Diabetes Complications; D004586:Electrophoresis; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006037:Glyoxal / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space; D008565:Membrane Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000378:metabolism; D013869:Thiolester Hydrolases; D024502:alpha-Tocopherol / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D003603:Cytotoxins; D017127:Glycation End Products, Advanced; D008565:Membrane Proteins; D010446:Peptide Fragments; D006037:Glyoxal; D011765:Pyruvaldehyde; C437985:THEM4 protein, human; D013869:Thiolester Hydrolases; D024502:alpha-Tocopherol