High-Protein Diet Linked to Lower Brain Mass in Alzheimer's Mouse Model

Caroline Cassels

October 23, 2009

October 23, 2009 — A high-protein diet has been linked to lower overall brain mass in transgenic mouse models of Alzheimer's disease (AD) — a finding that raises the possibility that such diets leave neurons more vulnerable to beta amyloid (Aβ) toxicity.

An international team of researchers led by Samuel Gandy MD, PhD, professor of neurology and psychiatry and associate director of the Alzheimer's Disease Research Center at the Mount Sinai School of Medicine, New York City, unexpectedly found that the brains of mice fed a high-protein, low-carbohydrate diet were 5% lower in weight than brains from their counterparts who were fed other types of diets.

"We don't know the reason for this finding, but it was very, very, obvious," Dr. Gandy said in an interview.

In clinical terms, patients with severe AD may experience a loss in brain mass of about 20%, so a 5% difference in brain weight, said Dr. Gandy, is "quite significant."

The study was published online October 21 in Molecular Neurodegeneration.

Effect of Dietary Composition

According to Dr. Gandy, research has shown that caloric restriction increases in longevity in lower animals and, more recently, in mammals. In addition, animal models of AD indicate that caloric-restrictive diets diminish AD pathology in mice.

"In this study we wanted to focus not so much on the caloric level of the diet but on the dietary composition and whether that made a difference to AD pathology biochemically and histologically," he said.

To examine how dietary composition modulates cerebral amyloidosis and neuronal integrity the researchers maintained 4 groups of TgCRND8 mice from 4 to 18 weeks of age on 1 of 4 diets:

  • Regular commercial chow

  • High-fat/low-carbohydrate custom chow (60 kcal% fat/30 kcal% protein/10 kcal% carbohydrate)

  • High-protein/low-carbohydrate custom chow (60 kcal% protein/30 kcal% fat /10 kcal% carbohydrate)

  • High-carbohydrate/low-fat custom chow (60 kcal% carbohydrate/30 kcal% protein/10 kcal% fat)

Lower Density of Neurons in the Hippocampus

At 18 weeks the mice were killed and their brains studied for wet weight, solubilizable Aβ content, amyloid plaque burden, and stereologic analysis of selected hippocampal subregions.

The authors compared the brain pathology in these mouse models of AD according to the diet they were fed. They also looked at the density of nerve cells in the hippocampus, as well as gross weight of the brains.

Not unexpectedly, the investigators found that mice that were fed a high-fat diet had higher increased levels of solubilizable Aβ, although the investigators detected no effect on plaque burden. This finding, said Dr. Gandy, is consistent with findings from previous research that show that a high-fat diet increases pathology in mouse models of AD.

In addition to the surprise finding that mice on a high-protein diet had brains that were 5% lighter than animals in the comparator groups, the investigators also found that although not statistically significant, there was a "clear trend" toward having a lower density of neurons in the hippocampus in mice that received the high-protein diet.

According to Dr. Gandy, if this finding is reflective of what is going on in the brain as a whole, it perhaps suggests that a high-protein diet makes neurons more sensitive to amyloid toxicity.

Don't Overinterpret

Dr. Gandy said although these findings are intriguing, they should not be overinterpreted.

"I wouldn't rush to overinterpret a mouse experiment, but it does raise the question of 'We should look to see if this also applies in humans,' " he said.

Dr. Gandy said his team has plans to conduct another similar experiment in a bid to replicate these findings. The researchers may also conduct a study of hospital records to look at outcomes in individuals, such as dialysis patients, who have been on high-protein diets long-term.

Although there are no immediate clinical recommendations, Dr. Gandy said the study highlights the benefits of a balanced diet.

"Every time we've looked an isolated dietary component in excess it seems to have a negative effect. Maybe the message here is that a balanced diet really is valuable and that you should get part of your calories from carbs, part from protein, and part from fat, and don't get carried away with one source over the other," said Dr. Gandy.

The authors have disclosed no relevant financial relationships.

Mol Neurodegener. Published online October 21, 2009.

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