7 June 2004. Oxidative stress has been postulated as a major factor in the pathology of a variety of neurodegenerative disorders, including Alzheimer’s disease (AD). However, evidence linking this type of stress to the major hallmark of AD, amyloid plaques, has been less than direct. Now, in this month’s Journal of Neurochemistry, Gunnar Gouras and colleagues at Cornell University, New York, show that knocking out superoxide dismutase in mice leads to accelerated accumulation of plaques.
Superoxide dismutase (SOD) is a major scavenger of the highly reactive oxygen species that are generated in mitochondria. Gouras and colleagues wondered how loss of the mitochondrial variant of the enzyme, which harbors a manganese atom at its catalytic core, would affect the accumulation of amyloidβ plaques in mice. To test this, first author Feng Li and colleagues crossed mice that are missing one copy of the MnSOD with mice that express human amyloid-β precursor protein (AβPP) that harbor mutations causing early-onset AD. These animals, or APP19959 mice as they are called, begin to accumulate amyloid plaques as early as three months old.
When Li examined the offspring, they found that those with only one copy of the MnSOD had protein markers of oxidative stress that were almost twice as high as in animals carrying two good copies of the dismutase. The authors also found that by four months old, Aβ was elevated by about 25 percent in brains of the MnSOD knockouts. These animals also had considerably increased plaque burden. When the authors measured plaques by immunohistochemistry, they found a ninefold increase in hippocampal, and an eightfold increase in cortical plaques. “To our knowledge,” write the authors, “our results are the first to show in vivo that a primary perturbation of free radical metabolism causes exacerbation of the amyloid pathology characteristic of AD.”
Recently, the association between oxidative stress and neurodegeneration has been strengthened by a variety of studies. Mutations that cause Parkinson’s disease, for example, have been linked to proteins that function in mitochondria, the major site for production of reactive oxygen species (see ARF related news story, and ARF related story). Connections to AD include studies that suggest a mitochondrial complex between Aβ and alcohol dehydrogenase promotes leakage of reactive oxygen species and cell death (see ARF related news story), and the identification of a carbonyl reductase, which is elevated in AD and which can protect against oxidative stress-induced neurodegeneration (see ARF related news story). All told, it seems that our mitochondria, the powerhouses that keep us going, may also be somewhat of an Achilles' heel for our aging brains.—Tom Fagan.
Li F, Calingasan NY, Yu F, Mauck WM, Toidze M, Almeida CG, Takahashi RH, Carlson GA, Beal MF, Lin MT, Gouras GK. Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J. Neurochem. 2004;89:1308-1312. Abstract