The plasma membrane redox system is impaired by amyloid β-peptide and in the hippocampus and cerebral cortex of 3xTgAD mice.
Membrane-associated oxidative stress has been implicated in the synaptic dysfunction and neuronal degeneration that occurs in Alzheimer's disease (AD), but the underlying mechanisms are unknown. Enzymes of the plasma membrane redox system (PMRS) provide electrons for energy metabolism and recycling of antioxidants. Here, we show that activities of several PMRS enzymes are selectively decreased in plasma membranes from the hippocampus and cerebral cortex of 3xTgAD mice, an animal model of AD. Our results that indicate the decreased PMRS enzyme activities are associated with decreased levels of coenzyme Q(10) and increased levels of oxidative stress markers. Neurons overexpressing the PMRS enzymes (NQO1 or cytochrome b5 reductase) exhibit increased resistance to amyloid β-peptide (Aβ). If and to what extent Aβ is the cause of the impaired PMRS enzymes in the 3xTgAD mice is unknown. Because these mice also express mutant tau and presenilin-1, it is possible that one or more of the PMRS could be adversely affected by these mutations. Nevertheless, the results of our cell culture studies clearly show that exposure of neurons to Aβ1-42 is sufficient to impair PMRS enzymes. The impairment of the PMRS in an animal model of AD, and the ability of PMRS enzyme activities to protect neurons against Aβ-toxicity, suggest enhancement PMRS function as a novel approach for protecting neurons against oxidative damage in AD and related disorders.
Hyun
Dong-Hoon
DH
Department of Life Science, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, South Korea. hyundh@ewha.ac.kr
Mughal
Mohamed R
MR
Yang
Hyunwon
H
Lee
Ji Hyun
JH
Ko
Eun Joo
EJ
Hunt
Nicole D
ND
de Cabo
Rafael
R
Mattson
Mark P
MP
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
D016229:Amyloid beta-Peptides; D014451:Ubiquinone; C024989:coenzyme Q10