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.
Reference
Ghoshal N, Smiley JF, DeMaggio AJ, Hoekstra MF, Cochran EJ, Binder LI, Kuret J.
A New Molecular Link Between the Fibrillar and Granulovacuolar Lesions of
Alzheimer's Disease. Am J Path 1999;155:1163-72.
Researcher
Dr. Jeffrey Kuret (614-688-5899)
Dept. of Medical Biochemistry
Ohio State University College of Medicine
kuret.3@osu.edu
University Media Contact
David Crawford (614-293-3737)
Medical Center Communications
Ohio State University
crawford.1@osu.edu
For scientific perspective on this work, contact either the NIGMS Office of Communications and Public Liaison (301-496-7301) to interview Dr. Richard Ikeda, program director in NIGMS' Division of Pharmacology, Physiology, and Biological Chemistry; or the NIA Public Information Office (301-496-1752) to interview Dr. Stephen Snyder, program director in the Neuroscience and Neuropsychology of Aging program at NIA.
Journal
American Journal Of Pathology