In a study presented at the annual meeting of the American Association for the Advancement of Science in Seattle this weekend, scientists with the US National Institute on Aging (NIA) said that alterations in fats - particularly cholesterol and ceramide - may contribute to a 'neurodegenerative cascade' that destroys neurons in Alzheimer's disease. Limiting accumulation of these fats in the brain might someday be able affect the course of the disease, they say.
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 have previously 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 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," he added.
In the lipids study, published online in the Proceedings of the National Academy of Sciences, the NIA team compared the brains of young mice to those of older mice in order to establish an association between ageing, 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."
Other researchers discussing ways to slow down the onset of Alzheimer's at the meeting included Carl W. Cotman, a neurochemist in the Institute for Brain Aging and Dementia at the University of California at Irvine. He presented work suggesting that the effects of ageing 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.
The number of people with dementia is steadily increasing. Alzheimer's disease is the most common form of dementia, making up 55 per cent of all cases of dementia. There are nearly 18 million people with dementia in the world.