Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment.
Oxidative stress, protein misfolding, protein complex formation, and detergent insolubility are biochemical features of Alzheimer's disease (AD). We tested the cause-and-effect relationships among these using MC65 human neuroblastoma cells that exhibit toxicity upon conditional expression of carboxy-terminal fragments (CTFs) of the human amyloid precursor protein (APP). Treatments with three different antioxidants (alpha-tocopherol, N-acetyl cysteine, and alpha-lipoic acid) or three different compounds (glycerol, trimethylamine-N-oxide, and 4-phenylbutyric acid) that have been described to have a "chemical chaperone" function in promoting protein folding all had a protective effect on MC65 cells and decreased markers of oxidative damage and accumulation of high molecular weight amyloid (A) beta-immunoreactive (IR) species. However, chaperones partially reduced detergent insolubility of the remaining Abeta-IR species, while antioxidants did not. These results suggest that protein misfolding associated with overexpression of APP CTFs promotes oxidative stress and cytotoxicity and contributes to formation of detergent-insoluble species that appear unrelated to cytotoxicity.
Woltjer
Randall L
RL
Department of Pathology, University of Washington, Box 359645, Harborview Medical Center, 300 Ninth Avenue, Seattle, WA 98104, USA. rwoltjer@u.washington.edu
McMahan
Wendy
W
Milatovic
Dejan
D
Kjerulf
John D
JD
Shie
Feng-Shiun
FS
Rung
Lisa G
LG
Montine
Kathleen S
KS
Montine
Thomas J
TJ
D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000737:chemistry; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D003902:Detergents / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism* / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D058225:Plaque, Amyloid / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D017510:Protein Folding; D012995:Solubility / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D003902:Detergents; D018832:Molecular Chaperones; D010446:Peptide Fragments