Cholesterol-Regulating Enzyme is a Promising New Target for Alzheimer's Prevention

by Jim Schnabel

March 8, 2016

More than thirty years have passed since scientists began to develop therapies aimed at blocking the processes that cause Alzheimer’s disease. Still they keep finding new targets.

The latest is an enzyme called Idol. Researchers have known for several years that it plays a key role in the pathways that lead to atherosclerosis, and thus might be a good target for new drugs to help prevent heart disease. They have now found evidence that targeting Idol in the brain may also help prevent Alzheimer’s—which suggests the development of Idol inhibitors as a potential new class of Alzheimer’s drug.

“We’re certainly interested in collaborating with pharma or biotech to do something like that,” said UCLA researcher Peter Tontonoz, one of the principal investigators for the new study.

Idol belongs to a class of enzymes (ubiquitin ligases) whose job essentially is to help tag various molecules for destruction by cellular waste-disposal systems—often as part of a feedback mechanism that keeps the levels of those molecules in the proper range. Tontonoz and colleagues reported, in a study published in Science in 2009, that one of Idol’s specific targets is the LDL receptor, which draws cholesterol-related LDL (low-density lipoprotein) particles into liver cells and other cell types from the bloodstream and thus helps control serum cholesterol levels. (“Idol” stands for: inducible degrader of the LDL receptor.)That and later studies suggested that inhibiting Idol would allow the numbers of LDL receptors to rise, and the more numerous LDL receptors would in turn draw down the serum cholesterol level.

LDL receptors are also expressed on brain cells, and there is evidence that they draw in not only LDLs and other lipoproteins, but also the Alzheimer’s-associated protein amyloid beta (Aβ). In experiments in an Alzheimer’s mouse model, also published in 2009, a group led by Washington University at St. Louis researcher David Holtzman, a Dana Alliance for Brain Initiatives (DABI) member, found that genetically boosting LDL receptor levels in the mice’s neurons lowered the levels of Aβ in the extracellular space outside those neurons, and thereby reduced the mice’s usual accumulation of Aβ “plaques” and associated brain inflammation.

For the new study, published in Science Translational Medicine, Tontonoz teamed up with Jungsu Kim, who was first author of the Holtzman lab’s study and subsequently formed his own lab at the Mayo Clinic in Jacksonville. Their aim was to test whether inhibiting Idol in the brain would boost LDL receptor levels on brain cells and thus show an Aβ-clearing effect like the one seen in the Holtzman study.

The team found initially that in mice, Idol does indeed appear to be the dominant regulator of LDL receptors in brain cells, particularly in microglial cells—the brain-resident immune cells that are cousins to the macrophages of the bloodstream. Mice bred with the Idol gene knocked out had many more LDL receptors on their microglia, and showed more modest increases in LDL receptors on their neurons, than standard mice.

The researchers then crossed the Idol knockout mice with the same Alzheimer’s mice used in the Holtzman lab study (APP/PS1 mice) and found that Aβ was much less evident in the brain at age seven months than it was in ordinary Idol-carrying Alzheimer’s mice. Even a line of Alzheimer’s mice that had just one copy of the Idol gene, rather than the usual two, showed a significant drop in brain Aβ—suggesting that the partial blocking of Idol, as from a drug therapy, could be effective.

The Idol-less mice also showed significant reductions in markers of brain inflammation, apparently due to having lower burdens of Aβ. Reductions in Aβ were seen in both the insoluble form that makes up amyloid plaques, and in the insoluble form which includes single copies of Aβ and the small aggregates (oligomers) that are thought to play the greatest role in triggering dementia. Microglial cells, rather than neurons, appeared to be the primary consumers of Aβ via their LDL receptors.

Tontonoz and colleagues have since been exploring the development of small-molecule inhibitors of Idol that could be put in pill form and clinically tested. “We’ve done some in-house screening for small molecules [that inhibit Idol], but realistically that’s a Big Pharma project,” he said. “Our academic interest is more along the lines of probing the mechanism, and identifying in more detail which cell types are involved.”

“I really liked the Idol paper,” said Gary Landreth, a researcher at Case Western Reserve University, and DABI member, who studies how the brain clears Aβ. “The outcomes are clear and logical. I think it could be a great target.”

Idol, Aβ, and the enduring mystery of apo-E

How does a boost in LDL receptors lead to a reduction of Aβ from the extracellular space in the brain?

That’s a question that researchers in this area have yet to answer. They are fairly certain, though, that the answer involves apolipoprotein E (apoE), a molecule that serves as a bulk carrier of LDLs and other lipids in the brain and bloodstream.

ApoE has been linked with Alzheimer’s since 1993. It is found mingled with Aβ in Alzheimer’s brain plaques, and one of its common inherited variants, apoE4,somehow brings a greatly increased risk of Alzheimer’s, along with a faster accumulation of Aβ and earlier age of onset in those who do get the disease. The apoE4 variant also brings an increased risk of heart disease and high serum LDL, among other conditions.

ApoE4 appears to be more ancient than the more common and healthy apoE3 variant, and E4’s prevalence, which averages about 14 percent worldwide, tends to be higher in populations whose ancestors lived near the equator and the poles. No one really knows why.

Scientists also are still debating what apoE does with respect to Aβ and why the E4 variant is so harmful. One hypothesis is that Aβ, particularly as it aggregates, tends to stick to lipids being transported by apo-E molecules; it thus hitches a ride on apo-E into microglia, via LDL receptors. The apoE4 variant would perhaps do its lipid-carrying job less efficiently than other variants, leaving more Aβ to accumulate outside brain cells. But for any apo-E variant more LDL receptors should mean greater apoE uptake and thus faster Aβ clearance. In support of this notion is the fact that, in both the recent Tontonoz-Kim study and the Holtzman lab’s earlier study, boosting LDL receptor levels strongly lowered extracellular levels of apoE along with Aβ. But there are at least several other theories still in play.

“Does apoE bind Aβ or do they separately bind the LDL receptor?” Tontonoz says. “We didn’t address that question in our study, but somebody needs to address it.”

“The apoE story remains enigmatic and I would say there is little new understanding,” said Landreth, though he added that “The LDL receptor linkage [to apoE] is very interesting and potentially important therapeutically.”

Testing of therapies that impact the LDL receptor and apoE pathways might help resolve the mystery. Landreth and colleagues have studied an off-the-shelf skin cancer drug, bexarotene, which boosts apoE production and has seemed to dramatically accelerate Aβ clearance from the brain—and improve memory performance—in Alzheimer’s mice.

Results of similar experiments in other laboratories have varied widely, and in a recent small-scale trial in human volunteers, according to Landreth, “the outcome was that in normal young individuals the drug is poorly blood-brain-barrier permeant. Thus, it is not likely to be of utility as a preventative agent and maybe not in MCI [mild cognitive impairment].” But he added that there may be hope for it as a treatment for people with established Alzheimer’s, in whom the blood-brain barrier tends to be relatively porous. In another recent small study in mild-to-moderate Alzheimer’s patients, he said, a separate team of investigators found a significant reduction in Aβ plaques in non-ApoE4 carriers, as measured by brain imaging, after just 30 days of bexarotene treatment.

“There are going to be new and I think exciting developments in this story,” Landreth said.