New Study May Explain How Fats Damage Neurons In Alzheimer's Patients

In a study released today at the 2004 AAAS (Triple-A-S) Annual Meeting in Seattle, and published online in the Proceedings of the National Academy of Sciences, scientists with the National Institute on Aging (NIA) suggest that alterations in fats--particularly cholesterol and ceramide--may contribute to a "neurodegenerative cascade" that destroys neurons in Alzheimer's disease. Further, the researchers suggest that the oxidative stress brought on by the presence of the toxic beta amyloid peptide seems to trigger the accumulation of ceramide and cholesterol. The ceramide in turn may trigger the death of nerve cells, the NIA's Mark P. Mattson said.

Lipids (fats) have been implicated in Alzheimer's disease, but only recently have researchers begun to understand their role, and their relationship to the beta amyloid that accumulates in the brains of people with the devastating neurodegenerative disease.

"We had suspected that changes in fat metabolism in the membranes of nerve cells played a role in Alzheimer's but we had not been able to establish a direct link," Mattson said. "With this study, we have been able to illustrate how alterations in membrane lipids can lead to neuronal dysfunction and death."

The new findings also provide an explanation for how antioxidants such as vitamin E might delay the onset of Alzheimer's, suggesting possible new directions for treatment of the disease: The NIA team first established that levels of ceramide and cholesterol were increased in brain cells from deceased Alzheimer's patients. They then found that beta amyloid beta peptide increases ceramide and cholesterol levels in cultured rat nerve cells, and that treatment with Vitamin E reduced the levels of ceramide and cholesterol, resulting in "a significant decrease in the number of neurons killed by the beta amyloid and oxidative stress. In addition, a small molecule inhibitor of ceramide production had the same effect.

Mattson noted that he and his colleagues are currently using a mouse model of Alzheimer's disease to study the impact that different lipids in the diet might have on learning and memory.

"For the moment, the implications are more for preventing Alzheimer's than for improving outcomes," said Mattson, Chief of NIA's Laboratory of Neurosciences.

Mattson joined other researchers on a panel at the AAAS Annual Meeting in Seattle for a discussion of ways to slow down the onset of Alzheimer's, which is projected to affect more than 13 million older Americans by 2050, unless ways are found to prevent or treat the disease. Susan Resnick, an investigator in the NIA's Laboratory of Personality and Cognition, presented the results of her recently published study regarding a possible link in older men between testosterone levels in the blood and Alzheimer's disease. Carl W. Cotman, a neurochemist in the Institute for Brain Aging and Dementia at the University of California at Irvine, presented work suggesting that the effects of aging on a dog's brain can be reversed by feeding the animals a diet that is high in antioxidants, and exposing them to "cognitive enrichment" activities that make them think. Benjamin Wolozin, an associate professor in the Department of Pharmacology of the Loyola University School of Medicine, discussed the promise of cholesterol-lowering statins in delaying the symptoms of Alzheimer's. Both Cotman and Wolozin received NIA support for the work they will present at the AAAS event.

In the lipids study, the NIA team compared the brains of young mice to those of older mice in order to establish an association between aging, oxidative stress and increased ceramide and cholesterol levels. They also measured levels of fats in tissue samples from two different regions of the brains of deceased Alzheimer's patients, and compared them to the same regions in the brains of deceased "neurologically-normal individuals."

The researchers found significantly higher levels of ceramide and cholesterol in the middle frontal gyrus of the Alzheimer's patients, when compared to the same region in a control group of normal brains. The amounts of these lipids and the extent of oxidative damage the scientists found increased with the severity of the disease. The cerebellum of the brains affected by Alzheimer's showed no increase in the level of the lipids, when compared to the cerebellum of the normal brains. The middle frontal gyrus is one brain region where the telltale amyloid deposits and neurofibrillary tangles indicate the presence of the disease in people with Alzheimer's.

"The involvement of cholesterol and ceramide in the neurotoxic actions of beta amyloid, and their strong associations with the way the Alzheimer's progresses, suggests a novel approach for therapeutic interventions," Mattson said. "Our work suggests that dietary modifications and drugs that inhibit the accumulation of ceramide and cholesterol may prove effective in suppressing the processes that lead to the disease."