TY - JOUR
T1 - Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid β-peptide (1-42), H2O2 and kainic acid
T2 - Implications for Alzheimer's disease
AU - Mohmmad Abdul, Hafiz
AU - Sultana, Rukhsana
AU - Keller, Jeffrey N.
AU - St. Clair, Daret K.
AU - Markesbery, William R.
AU - Butterfield, D. Allan
PY - 2006/3
Y1 - 2006/3
N2 - Oxidative stress is observed in Alzheimer's disease (AD) brain, including protein oxidation and lipid peroxidation. One of the major pathological hallmarks of AD is the brain deposition of amyloid beta-peptide (Aβ). This 42-mer peptide is derived from the β-amyloid precursor protein (APP) and is associated with oxidative stress in vitro and in vivo. Mutations in the PS-1 and APP genes, which increase production of the highly amyloidogenic amyloid β-peptide (Aβ42), are the major causes of early onset familial AD. Several lines of evidence suggest that enhanced oxidative stress, inflammation, and apoptosis play important roles in the pathogenesis of AD. In the present study, primary neuronal cultures from knock-in mice expressing mutant human PS-1 and APP were compared with those from wild-type mice, in the presence or absence of various oxidizing agents, viz, Aβ(1-42), H2O 2 and kainic acid (KA). APP/PS-1 double mutant neurons displayed a significant basal increase in oxidative stress as measured by protein oxidation, lipid peroxidation, and 3-nitrotyrosine when compared with the wild-type neurons (p < 0.0005). Elevated levels of human APP, PS-1 and Aβ(1-42) were found in APP/PS-1 cultures compared with wild-type neurons. APP/PS-1 double mutant neuron cultures exhibited increased vulnerability to oxidative stress, mitochondrial dysfunction and apoptosis induced by Aβ(1-42), H 2O2 and KA compared with wild-type neuronal cultures. The results are consonant with the hypothesis that Aβ(1-42)-associated oxidative stress and increased vulnerability to oxidative stress may contribute significantly to neuronal apoptosis and death in familial early onset AD.
AB - Oxidative stress is observed in Alzheimer's disease (AD) brain, including protein oxidation and lipid peroxidation. One of the major pathological hallmarks of AD is the brain deposition of amyloid beta-peptide (Aβ). This 42-mer peptide is derived from the β-amyloid precursor protein (APP) and is associated with oxidative stress in vitro and in vivo. Mutations in the PS-1 and APP genes, which increase production of the highly amyloidogenic amyloid β-peptide (Aβ42), are the major causes of early onset familial AD. Several lines of evidence suggest that enhanced oxidative stress, inflammation, and apoptosis play important roles in the pathogenesis of AD. In the present study, primary neuronal cultures from knock-in mice expressing mutant human PS-1 and APP were compared with those from wild-type mice, in the presence or absence of various oxidizing agents, viz, Aβ(1-42), H2O 2 and kainic acid (KA). APP/PS-1 double mutant neurons displayed a significant basal increase in oxidative stress as measured by protein oxidation, lipid peroxidation, and 3-nitrotyrosine when compared with the wild-type neurons (p < 0.0005). Elevated levels of human APP, PS-1 and Aβ(1-42) were found in APP/PS-1 cultures compared with wild-type neurons. APP/PS-1 double mutant neuron cultures exhibited increased vulnerability to oxidative stress, mitochondrial dysfunction and apoptosis induced by Aβ(1-42), H 2O2 and KA compared with wild-type neuronal cultures. The results are consonant with the hypothesis that Aβ(1-42)-associated oxidative stress and increased vulnerability to oxidative stress may contribute significantly to neuronal apoptosis and death in familial early onset AD.
KW - Alzheimer's disease
KW - Amyloid precursor protein
KW - Oxidative stress
KW - Presenilin-1
KW - β-amyloid peptide (1-42)
UR - http://www.scopus.com/inward/record.url?scp=33645106304&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645106304&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2005.03647.x
DO - 10.1111/j.1471-4159.2005.03647.x
M3 - Article
C2 - 16478525
AN - SCOPUS:33645106304
SN - 0022-3042
VL - 96
SP - 1322
EP - 1335
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 5
ER -