Want to fight Alzheimer's disease? Target insulin signaling.

In a study published in the Dec. 8, 2004, issue of the Journal of Neuroscience, scientists presented new supporting evidence for that seeming non-sequitur.

Previous lines of research had shown that diabetics are at increased risk of developing Alzheimer's disease. In fact, at least one medication that is aimed at treating Type II diabetes, GlaxoSmithKline plc's Avandia (rosiglitazone maleate), is in Phase II trials for Alzheimer's disease, though it bears mentioning that the drug seems to offer hope as a modern cure-all: According to the NIH website www.clinicaltrials.gov, it also is in trials for thyroid cancer, inflammatory bowel disease, congestive heart failure and HIV infection.

People with certain genetic risk factors for Alzheimer's have higher levels of a peptide known as Aß. That monomer itself is not harmful - there is some evidence that it is neuroprotective - but when it aggregates, it forms ß-amyloid peptide, one of the hallmarks of Alzheimer's disease.

There also are non-genetic factors suggesting a relationship between insulin signaling and Alzheimer's disease. Patients with no known genetic risk factors for Alzheimer's disease also have high plasma levels of Aß. Poor glucose control is associated with memory problems and atrophy of the hippocampus, part of the brain known to be important for the formation of new memories. (See BioWorld Today, Feb 13, 2003.)

"At some level, [Aß] is a quantitative issue. Everybody is making the stuff, but normally, the balance [between Aß monomer and ß-amyloid polymer] is good," said Greg Cole, who is associate director of the Geriatric Research Education Clinical Center at the Greater Los Angeles Veteran's Administration Medical Center and associate director of the University of California at Los Angeles Alzheimer's Disease Research Center. The research he and his colleagues have published suggest that one way to maintain a good balance is through insulin-degrading enzyme.

In spite of its name, insulin-degrading enzyme also is known to degrade Aß monomers.

"People have been trying to modulate insulin signaling at the level of production," Cole said. "Now, there is also increased focus on targeting the level of degradation." The chromosomal region containing the gene for insulin-degrading enzyme previously had been identified as a region containing a risk gene for Alzheimer's disease via genetic linkage analysis.

From The Periphery Into The Brain

Cole's group first tested the idea that insulin-degrading enzyme might play a role in Alzheimer's disease in isolated hippocampal cells from rats. They found that stimulating those cells with insulin led to increased expression of insulin-degrading enzyme. That increase could be blocked by inhibiting PI3 kinase, suggesting it is dependent on activation of that kinase. The activation ultimately led to increased phosphorylation and activation of Akt kinase, a downstream target of PI3. Control experiments showed those changes in the insulin-stimulated cells were not due to either changes in cell survival rates compared to controls, or the appearance of new cells - for example, from stem cells contaminating the cell cultures.

The researchers also compared brain tissue from subjects that had died of Alzheimer's disease to matched controls. There, immuno-staining revealed a decrease in both insulin-degrading enzyme and a subunit of PI3 kinase (assessed by measuring a subunit) in the brains of patients with Alzheimer's disease. Decreased expression in both proteins was correlated, whereas decrease in another protein, post-synaptic density-95, that also was downregulated in Alzheimer's disease, did not correlate with levels of insulin-degrading enzyme.

In a final experiment, the scientists tried to induce an IDE deficiency by feeding transgenic mice that show a number of Alzheimer's-like characteristics a diet high in safflower oil, which previously had been shown to accelerate Alzheimer's disease-like symptoms in mice. Despite its oily sound, the diet is not high-fat - the control diet, consisting of regular lab chow, contained more fat than the safflower diet. However, the high-safflower oil diet (called the "Bad" diet in the paper) had a reduced amount of poly-unsaturated fats, and was particularly depleted in omega-3 fatty acids, compared to standard lab chow.

Fifteen weeks on the Bad diet reduced protein and mRNA levels of both IDE and PI3 kinase (again as assessed by a subunit), leading, in turn, to increased levels of Ab monomers.

"The moral of the story is diets that cause peripheral insulin resistance also limit the brain's insulin-signaling pathway and reduce [degradation] of the amyloid peptide that can accumulate and cause Alzheimer's," Cole said. He added that "as you age and start to put on weight, your degrading enzymes go down. Maybe the same thing is going on in the brain and that's what puts you at risk for Alzheimer's disease."

He pointed out that "in this paper, we're reporting modest but significant effects. And that's a good thing. In general, [degradation enzymes] degrade many things. So you don't want to change the levels too much."