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Sci. Aging Knowl. Environ., 13 November 2002
Vol. 2002, Issue 45, p. nw154
[DOI: 10.1126/sageke.2002.45.nw154]

NOTEWORTHY ARTICLES

Metal for Mettle

Shortage of iron-containing molecule might contribute to Alzheimer's disease and aging

Mary Beckman

http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/45/nw154

Key Words: cytochrome c oxidase • ferrochelatase • {beta}-amyloid precursor protein • metal homeostasis

Abstract: Like cars running out of gas, the brains of patients with Alzheimer's disease sputter and slow. New data from cultured human and rat brain cells suggest that loss of heme, an iron-containing molecule whose amounts decrease with age, might contribute to reduced energy production in the demented brains. The results provide a possible new link between the metabolic machinery in cells and cognitive decline due to age-related neurodegeneration.

Hallmark protein plaques and tangles pockmark the brains of Alzheimer's disease patients, and a paucity of iron and abnormally low metabolic activity throw off neurological function. Previously, scientists showed that mitochondria, the cell's energy-producing units, malfunction in the diseased organs and that one module of the mitochondrial power plant, complex IV, is half as active as normal. That breakdown might arise from a heme shortage, postulated cell biologist Hani Atamna of Children's Hospital Oakland Research Institute in California, who had shown that human skin cells deprived of heme had reduced amounts of complex IV. Because heme concentrations decrease with age, Atamna and colleagues investigated whether losing the iron carrier cripples neuron function.

To determine how heme deficiency affects human brain cells, they first blocked heme production in two different types of brain cell cultures: one that can mature into neurons and another of astrocytes, which feed neurons within brains. The team measured the amount of complex IV proteins present and found that lack of heme eliminated them in both types. Furthermore, quantities of full-length soluble APP, the protein that gives rise to plaques, decreased in the human cell cultures and in fresh rat brain cells as aggregated APP appeared, suggesting a role for heme in proper processing of APP. In addition, cells without heme produced extra nitric oxide synthase, an enzyme that makes destructive free radicals that cause oxidative stress (see "The Two Faces of Oxygen"). Iron scarcity in people damages mitochondria and increases oxidative stress, and the results suggest that a dearth of heme might cause those changes.

To test whether heme deficiency thwarts precursor cells' ability to mature into neurons properly, the team added nerve growth factor to the neuron precursor culture. The substance caused normal cells to grow extensions and develop into neurons, but cells lacking the iron carrier balled up and died. Together, the observations raise the possibility that heme links the impaired metabolism, abnormal APP processing, mitochondrial decay, and neuronal death previously observed in Alzheimer's patients. "We had all these observations, and no one could offer a mechanism," says Atamna. Next, the team plans to study mice with defects in heme synthesis to help clarify the molecule's role in neurodegeneration of live animals.

Neurologist William Davis Parker of the University of Virginia, Charlottesville, says, "The mechanism they're proposing--that the availability of heme could be an issue--is novel." Additional experiments are needed to determine whether heme production is altered in diseased tissue, he adds. If so, heme might help iron out some wrinkles in the study of aging.

--Mary Beckman; suggested by Amir Sadighi Akha

H. Atamna, D. W. Killilea, A. N. Killilea, B. N. Ames, Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. Proc. Natl. Acad. Sci. U.S.A., 4 November 2002 [e-pub ahead of print]. [Abstract] [Full Text]

Citation: M. Beckman, Metal for Mettle. Science's SAGE KE (13 November 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/45/nw154







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