Atlanta, GA - A new study has shown a high-fat, high-cholesterol diet induces neuroinflammation and impairs working memory in mice—a finding that confirms and extends previous research and may have major implications for staving off and treating cognitive impairment associated with Alzheimer's disease (AD) in humans [1].

According to principal investigator Dr Narayan Bhat (Medical University of South Carolina, Charleston), other studies demonstrating this relationship have been conducted in transgenic animals, which are genetically predisposed to developing AD. However, this study is the first to show high cholesterol also adversely affects working memory in normal animals.

"It is difficult to address the dietary effect on transgenic animals because they are already predisposed to developing AD symptoms. We wanted to look at normal mice to see what happens to their memory. To the best of our knowledge, ours is the first study to show that a high-fat, high-cholesterol diet causes neuroinflammation in nontransgenic mice. Preliminary indications are that the brains of these mice also contain increased levels of amyloid beta, a protein known to be associated with Alzheimer's pathology," Bhat said.

The study's findings were recently presented at Neuroscience 2006, the annual meeting of the Society of Neuroscience.

The animals were fed a high-cholesterol, high-fat diet for two months. At weeks 7 and 8 of the study, the mice were tested daily for memory performance, which was then compared with a control group of mice that were fed a normal diet.

In addition, the investigators conducted a parallel study in a group of LDL-receptor-knockout (LDLRKO) mice.

With a three- to fourfold increase in the number of memory errors, normal mice on the high-fat diet had significantly poorer memory performance than controls. The hypercholesterolemic LDLRKO mice, on the other hand, showed signs of impaired memory and neuroinflammation irrespective of diet, which were exacerbated with high-fat, high-cholesterol feeding.

This finding indicates it may not be increased cholesterol levels per se that adversely affect memory but the associated inflammation. Interestingly, Bhat said, recent clinical studies have shown patients on statin therapy to lower their cholesterol levels have a lower incidence of AD, a finding that has been attributed to the agents' anti-inflammatory rather than cholesterol-lowering effect. Similar findings have been reported in patients taking aspirin and other nonsteroidal anti-inflammatory drugs.

When the investigators looked at the biochemical changes in the brains of normal mice fed a high-fat diet vs controls, they found the hippocampi showed inflammatory markers, including increased levels of CD45, a microglial marker, and GFAP, an astrocyte marker. Furthermore, increased levels of A-40, an early marker of AD, were also observed.

"Normally these microglia act as scavenger cells and clean up cell debris. But if they are activated chronically they produce toxic mediators, including free radicals and cytokines, that damage neurons and their synaptic connections, which are necessary for memory formation," said Bhat.

If these results are confirmed, they have major implications for AD prevention. "We know that 95% of Alzheimer's disease is sporadic, with no known genetic connection, other than allelic differences in APOE, a known cholesterol carrier protein that does not, by itself, cause AD but may favor the incidence of the disease. If much of it is due to lifestyle or environmental factors that, to a large degree, are modifiable, this offers the hope that we can prevent AD development," he said.

Such strategies he added could include low-fat diets or potentially diets high in polyunsaturated fats. In addition, the connection between diet-induced neuroinflammatory changes and memory deficit emphasizes the potential therapeutic usefulness of anti-inflammatory treatment, including cholesterol-lowering agents or select NSAID therapy.