OCT 1, 1999, M2 Communications - Scientists have discovered a new
molecular marker for Alzheimer's disease--a normal cellular protein
that piles up in nerve cells ravaged by the disease.
Alzheimer's disease (AD) is an irreversible disorder that worsens
with time. As a result of damage to brain cells, AD produces its
hallmark symptoms: mild forgetfulness that progresses to severe and
debilitating memory loss. Except for a minority of cases (6 to 7
percent) caused by faulty genes, scientists don't yet know what causes
this devastating disease that affects an estimated 4 million people in
the United States.
A research team supported by the National Institutes of Health (NIH)
examined the brains of people who had died from AD and found abnormally
large amounts of the cellular signpost--a normal enzyme in the body
called casein kinase-1 (CK-1). The researchers found that a high level
of CK-1 was present in nerve cells inside cellular sacs called
vacuoles. The findings indicate that a high CK-1 level in vacuoles may
be a useful marker for AD, along with the two other long- recognized
cellular abnormalities, or "lesions," associated with the disease:
plaques and tangles.
The work appears in the October issue of the "American Journal of
Pathology". Previous research had already shown that such vacuoles,
called "GVD (granulovacuolar degeneration) bodies," were a prominent
feature in about half of all AD cases. Scientists also already knew
that the vacuoles tended to accumulate in a region of the brain called
the hippocampus that is particularly vulnerable in AD, and is normally
very important for learning and memory. Nonetheless, GVD bodies have
remained poorly understood by scientists because they have been
stubbornly difficult to locate within autopsied brain tissue. Until
now, no good markers for GVD bodies were available to scientists
studying AD.
The new work not only enables researchers to use CK-1 as a molecular
label for studying GVD bodies, but also forges a link between GVD
bodies and the more commonly studied plaques and tangles typical of AD
brains.
"The most important conclusion from our work is the existence of a
molecular connection between the different lesions of Alzheimer's
disease," said Dr. Jeffrey Kuret of Ohio State University and senior
author of the new study. Other team members were from Northwestern
University Medical Center and Rush Presbyterian Medical Center (both in
Chicago), and ICOS Corporation (in Bothell, Washington).
Dr. Kuret made the recent discovery while investigating the workings
and whereabouts of the CK-1 enzyme, a protein called a kinase that adds
molecular tags called phosphate groups to a host of cellular
components. The researchers had a suspicion that CK-1 might add
phosphate tags to a protein called "tau," which is present in AD
plaques, tangles, and GVD bodies. Normally, tau's job is to assemble
proteins called microtubules--the cell's structural scaffolding
apparatus--that stretch from one end of a nerve cell to the other to
ferry nutrients and structural components. Tau gets into trouble and
cannot keep its proper structure, scientists believe, when it acquires
too many phosphate tags.
Putting his suspicions to the test, Dr. Kuret searched for CK-1 in
the brain tissue of people who had died from AD.
The hunch proved correct: Dr. Kuret and his team turned up a 30-fold
increase of one particular form of CK-1 inside GVD bodies within the
hippocampus region of AD brains. This is the largest preponderance of a
kinase yet discovered in AD brain tissue. The results tantalizingly
suggest that CK-1 might play a role in setting the stage for, or in
accelerating, the brain cell death associated with AD. However, firm
proof of this idea awaits a much more detailed study of GVD bodies and
their role in AD and other similar neurodegenerative diseases.
Although Dr. Kuret's work began as a basic study probing how a
fundamental enzyme helps the cellular skeleton assemble, it now
provides insight into a disease-related problem, said Dr. Richard
Ikeda, a biochemist at the National Institute of General Medical
Sciences, a component of the NIH that partially funded the work. "In
this case, basic research revealed unexpected relationships between
normal processes and disease," he said.
Dr. Kuret's findings should enable new experiments aimed at
understanding the nature of AD, according to Dr. Stephen Snyder, a
neurobiologist at the National Institute on Aging, another NIH funding
source for the work.
"The isolation and in-depth analysis of GVD bodies could provide
valuable clues useful not only for the diagnosis of AD, but in gaining
a better understanding of the disease," said Dr. Snyder.
Many researchers have been searching for candidate kinases-- of which
hundreds exist--that might act upon tau and convert it to a
phosphate-laden jumble of ineffective protein. Pinpointing such a
culprit might aid in the design of inhibitors to block this process and
prevent ensuing nerve damage and cell death. Several such kinases have
been found, but only in test-tube experiments, which are notoriously
different from living systems.
No doubt the complete story will not be a simple one; for a disease
as complicated as AD, scientists reason that many proteins may
collectively contribute toward causing and perpetuating this
debilitating disease.
Yet researchers in the field welcome the discovery of CK-1 and other
identifiable disease-specific features, called "biomarkers," that can
serve as sentinels of disease in autopsied brains. Improvements in
technology on the horizon suggest that such biomarkers may soon offer
promise in diagnosing early-stage AD in living brains--while the
opportunity for therapeutic intervention still exists.
