Alzheimer’s damage might start off early

The seeds of mental destruction may be sown long before Alzheimer’s disease visibly mars the brain, according to two new animal studies.

The brains of people with advanced Alzheimer’s disease often shrink drastically while accumulating many deposits, or plaques, of a protein called beta-amyloid (SN: 8/5/95, p. 89). It’s no surprise that the most popular theory for the origins of the disease points to these plaques.

The new studies, however, lend support to a different scenario. In it, an overabundance of free-floating beta-amyloid molecules catalyzes the creation of reactive forms of oxygen–called free radicals. These radicals initiate a cell-destroying process known as oxidative stress. According to this scenario, the protein plaques aren’t the initial cause of Alzheimer’s devastating symptoms but rather the result of the cells’ desperate attempts to stem damage from the free radicals.

Although essential for life, oxygen can also be highly toxic, says Domenico Praticò of the University of Pennsylvania School of Medicine in Philadelphia. As cells use oxygen, they transform some of it into free radicals. The body’s systems for mopping up free radicals can malfunction or become swamped, leading to oxidative stress.

Praticò and his colleagues suspected that oxidative stress might precede the more obvious plaque formation in the brains of Alzheimer’s patients. From previous research, they knew that people with mild cognitive impairment have more free radicals in their brains than people of the same age without early Alzheimer’s symptoms do. The researchers also knew that protein plaques develop unusually early in genetically engineered mice that overproduce the beta-amyloid protein.

In the June 15 Journal of Neuroscience, the researchers report that oxidative stress appears in the brains of these engineered mice at only 8 weeks of age, which makes them roughly equivalent to teenagers. The scientists speculate that this oxidative stress stimulates the overgeneration of beta-amyloid, which then shows up months later in the form of plaques.

In the other study, Ashley Bush of Massachusetts General Hospital in Boston and his international team of researchers illuminate the other side of this free-radical-plaque equation.

In the presence of copper atoms in the brain, beta-amyloid can act as an enzyme that generates free radicals in the form of hydrogen peroxide. When concentrations of free radicals soar, zinc in the brain interacts with beta-amyloid and plaques result. This takes the dangerous copper-beta-amyloid combos out of circulation. Bush says this biochemical sequence helps explain why a certain metal-removing antibiotic seems to stop plaque formation (SN: 12/2/00, p. 360).

At high-enough concentrations, however, hydrogen peroxide can damage the plaques. This exposes copper atoms that had been bound up in the plaques. The copper then can catalyze the formation of more free radicals, Bush’s team reports in the June Neuron. When this happens, the initially protective plaques do in fact become part of the problem, says Bush.

Praticò’s study has significant implications about a “yin-yang” relationship between oxidative stress and beta-amyloid in Alzheimer’s disease, comments Simon Melov of the Buck Institute in Novato, Calif., where he investigates the chemical processes of aging. Melov says that he finds Bush’s study particularly exciting because it shows new properties of the protein plaques that might be exploited in novel therapeutic approaches.

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