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.
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.
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.
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.
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.
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.
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.
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.
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
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.”
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
a boost in LDL receptors lead to a reduction of Aβ from the extracellular space
in the brain?
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.
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.
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.”
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.”
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.
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
are going to be new and I think exciting developments in this story,” Landreth