Abstract
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 (α-tocopherol, N-acetyl cysteine, and α-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) β-immunoreactive (IR) species. However, chaperones partially reduced detergent insolubility of the remaining Aβ-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.
Original language | English (US) |
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Pages (from-to) | 427-437 |
Number of pages | 11 |
Journal | Neurobiology of Disease |
Volume | 25 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2007 |
Externally published | Yes |
Keywords
- Alzheimer's disease
- Amyloid precursor protein
- Antioxidants
- Chaperones
- Unfolded protein response
ASJC Scopus subject areas
- Neurology