Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment

Randall (Randy) Woltjer, Wendy McMahan, Dejan Milatovic, John D. Kjerulf, Feng Shiun Shie, Lisa G. Rung, Kathleen S. Montine, Thomas J. Montine

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)427-437
Number of pages11
JournalNeurobiology of Disease
Volume25
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

Fingerprint

Amyloid beta-Protein Precursor
Detergents
Oxidative Stress
Antioxidants
Thioctic Acid
Tocopherols
Protein Folding
Heat-Shock Proteins
Neuroblastoma
Amyloid
Glycerol
Cysteine
Alzheimer Disease
Proteins
Molecular Weight

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Antioxidants
  • Chaperones
  • Unfolded protein response

ASJC Scopus subject areas

  • Neurology

Cite this

Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment. / Woltjer, Randall (Randy); McMahan, Wendy; Milatovic, Dejan; Kjerulf, John D.; Shie, Feng Shiun; Rung, Lisa G.; Montine, Kathleen S.; Montine, Thomas J.

In: Neurobiology of Disease, Vol. 25, No. 2, 02.2007, p. 427-437.

Research output: Contribution to journalArticle

Woltjer, Randall (Randy) ; McMahan, Wendy ; Milatovic, Dejan ; Kjerulf, John D. ; Shie, Feng Shiun ; Rung, Lisa G. ; Montine, Kathleen S. ; Montine, Thomas J. / Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment. In: Neurobiology of Disease. 2007 ; Vol. 25, No. 2. pp. 427-437.
@article{dfaa943e77b0453ead48d75680ac4f0c,
title = "Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment",
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.",
keywords = "Alzheimer's disease, Amyloid precursor protein, Antioxidants, Chaperones, Unfolded protein response",
author = "Woltjer, {Randall (Randy)} and Wendy McMahan and Dejan Milatovic and Kjerulf, {John D.} and Shie, {Feng Shiun} and Rung, {Lisa G.} and Montine, {Kathleen S.} and Montine, {Thomas J.}",
year = "2007",
month = "2",
doi = "10.1016/j.nbd.2006.10.003",
language = "English (US)",
volume = "25",
pages = "427--437",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment

AU - Woltjer, Randall (Randy)

AU - McMahan, Wendy

AU - Milatovic, Dejan

AU - Kjerulf, John D.

AU - Shie, Feng Shiun

AU - Rung, Lisa G.

AU - Montine, Kathleen S.

AU - Montine, Thomas J.

PY - 2007/2

Y1 - 2007/2

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Amyloid precursor protein

KW - Antioxidants

KW - Chaperones

KW - Unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=33846301100&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846301100&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2006.10.003

DO - 10.1016/j.nbd.2006.10.003

M3 - Article

C2 - 17141508

AN - SCOPUS:33846301100

VL - 25

SP - 427

EP - 437

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

IS - 2

ER -