TY - JOUR
T1 - Rodent Aβ(1-42) exhibits oxidative stress properties similar to those of human Aβ(1-42)
T2 - Implications for proposed mechanisms of toxicity
AU - Boyd-Kimball, Debra
AU - Sultana, Rukhsana
AU - Mohmmad-Abdul, Hafiz
AU - Butterfield, D. Allan
PY - 2004
Y1 - 2004
N2 - Alzheimer's disease is a neurodegenerative disorder associated with aging and cognitive decline. Amyloid beta peptide (1-42) [Aβ(1-42)] is a primary constituent of senile plaques - a hallmark of Alzheimer's disease - and has been implicated in the pathogenesis of the disease. Previous studies have shown that methionine residue 35 of β(1-42) may play a critical role in Aβ(1-42)-mediated oxidative stress and neurotoxicity. Several additional mechanisms of neurotoxicity have been proposed, including the role of Cu(II) binding and reduction to produce hydrogen peroxide and the role of peptide aggregation. It has been reported that rodent Aβ is less likely to form larger β-sheet structures, and consequently, large aggregates. As a consequence of the lack of deposition of the peptide in rodent brain, rodent Aβ has been proposed to be non-toxic. Additionally, the sequence of the rodent variety of Aβ(1-42) contains three amino acid substitutions compared to the human sequence. These substitutions include the shift of arginine 5, trysosine 10, and histidine 13 to glycine, phenylalanine, and arginine, respectively. This shift in sequence within the Cu(II) binding region of the peptide results in a decrease in the ability of the rodent Aβ peptide to reduce Cu(II) to Cu(I) compared to the human Aβ peptide. As a result of the effect of the amino acid variations on the ability of the rodent peptide to reduce Cu(II) to Cu(I) compared to the human peptide, the rodent β has been proposed to lack oxidative stress properties. In this study, the oxidative stress and neurotoxic properties of rodent β(1-42) [Aβ(1-42)Rat] were evaluated and compared to those of human Aβ(1-42). Both human Aβ(1-42) and β(1-42)Rat were found to have a significant effect on neuronal DNA fragmentation, loss of neuritic networks, and cell viability. β(1-42) Rat was found to cause a significant increase in both protein oxidation and lipid peroxidation, similar to Aβ(1-42), both of which were inhibited by the lipid-soluble, chain breaking antioxidant vitamin E, suggesting that reactive oxygen species play a role in the Aβ-mediated toxicity. Taken together, these results suggest that Cu(II) reduction may not play a critical role inβ(1-42)Rat-induced oxidative stress, and that the oxidative stress exhibited by this peptide may be a consequence of the presence of methionine 35, similar to the findings associated with the native human β(1-42) peptide.
AB - Alzheimer's disease is a neurodegenerative disorder associated with aging and cognitive decline. Amyloid beta peptide (1-42) [Aβ(1-42)] is a primary constituent of senile plaques - a hallmark of Alzheimer's disease - and has been implicated in the pathogenesis of the disease. Previous studies have shown that methionine residue 35 of β(1-42) may play a critical role in Aβ(1-42)-mediated oxidative stress and neurotoxicity. Several additional mechanisms of neurotoxicity have been proposed, including the role of Cu(II) binding and reduction to produce hydrogen peroxide and the role of peptide aggregation. It has been reported that rodent Aβ is less likely to form larger β-sheet structures, and consequently, large aggregates. As a consequence of the lack of deposition of the peptide in rodent brain, rodent Aβ has been proposed to be non-toxic. Additionally, the sequence of the rodent variety of Aβ(1-42) contains three amino acid substitutions compared to the human sequence. These substitutions include the shift of arginine 5, trysosine 10, and histidine 13 to glycine, phenylalanine, and arginine, respectively. This shift in sequence within the Cu(II) binding region of the peptide results in a decrease in the ability of the rodent Aβ peptide to reduce Cu(II) to Cu(I) compared to the human Aβ peptide. As a result of the effect of the amino acid variations on the ability of the rodent peptide to reduce Cu(II) to Cu(I) compared to the human peptide, the rodent β has been proposed to lack oxidative stress properties. In this study, the oxidative stress and neurotoxic properties of rodent β(1-42) [Aβ(1-42)Rat] were evaluated and compared to those of human Aβ(1-42). Both human Aβ(1-42) and β(1-42)Rat were found to have a significant effect on neuronal DNA fragmentation, loss of neuritic networks, and cell viability. β(1-42) Rat was found to cause a significant increase in both protein oxidation and lipid peroxidation, similar to Aβ(1-42), both of which were inhibited by the lipid-soluble, chain breaking antioxidant vitamin E, suggesting that reactive oxygen species play a role in the Aβ-mediated toxicity. Taken together, these results suggest that Cu(II) reduction may not play a critical role inβ(1-42)Rat-induced oxidative stress, and that the oxidative stress exhibited by this peptide may be a consequence of the presence of methionine 35, similar to the findings associated with the native human β(1-42) peptide.
KW - Alzheimer's disease
KW - Amyloid β-peptide
KW - Oxidative stress
KW - Rodent amyloid β-peptide
UR - http://www.scopus.com/inward/record.url?scp=12844276303&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=12844276303&partnerID=8YFLogxK
U2 - 10.3233/JAD-2004-6509
DO - 10.3233/JAD-2004-6509
M3 - Article
C2 - 15505374
AN - SCOPUS:12844276303
SN - 1387-2877
VL - 6
SP - 515
EP - 525
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 5
ER -