Neurology:
Alzheimer's Plaques Reversed in Mice by Blocking Cholesterol Pathway
Metabolism:
Cellular Stress Appears to Link Obesity, Diabetes
Structural Biology:
Interdisciplinary Team Yields High-res Clathrin Model
Pathology:
Blood Flow Mechanics Affect Genetics in Vascular Cells
School History:
Book and Forum Recognize Achievement of African Americans at HMS
Medical Education:
Education Reform Aims for Longitudinal Clinical Experience
Muscle Loss Pathways Proliferate
Fine-particle Pollution Linked to Blood Pressure Boost
Human Cell Therapy Center Created at CBR Institute
Lieberman to Head Faculty Affairs
Five Faculty Members Become AAAS Fellows
Ground Broken for New Fenway Housing
Grant Funds HSPH Initiative for Preparedness Against Terrorism
Long-term Care: Averting a National Crisis
Alzheimer's Plaques Reversed in Mice by Blocking Cholesterol Pathway
Accumulation of amyloid-beta peptides has been correlated with the devastating neurodegeneration that plagues the Alzheimer's disease brain. So one challenge for the medical community has been to devise strategies to rid the brain of excess amyloid-beta.
Staining sections of the cerebral cortex for amyloid-beta shows that female mice given the ACAT inhibitor CP-113,818 (right) have remarkably fewer amyloid plaques than littermates treated with a placebo (left). (Image courtesy of Dora Kovacs and Neuron)
In theory, this could be accomplished by promoting removal of the peptides or by stopping their production. In practice, both approaches have proven difficult. Though there is hope that a vaccine can be developed to clear the peptides from the brain, this intervention suffered a setback during a recent clinical trial due to adverse immune reactions in a small number of patients. Alternative strategies such as inhibiting the proteases that produce the peptides are in the early phases of development.
Yet is there another approach? Perhaps. In the Oct. 14 Neuron, an international collaboration led by Dora Kovacs, HMS assistant professor of neurology at Massachusetts General Hospital, reports arresting the progression of Alzheimer's-like pathology in a mouse model of the disease. "We have reduced production of amyloid-beta, almost eliminated amyloid plaques, and improved cognitive function in these animals," said Kovacs. The strategy? Targeting cholesterol metabolism.
The Cholesterol Connection
The sweeping improvement in the mice was elicited by a small molecule called CP-113,818, an inhibitor of acyl-coenzyme A: cholesterol acyltransferase, or ACAT, which esterifies membrane-bound cholesterol, redistributing it into intracellular droplets. ACAT inhibitors slow down this process and slightly increase the amount of cholesterol in the cell membrane.
| "We have reduced production of amyloid-beta, almost eliminated amyloid plaques, and improved cognitive function in these animals." |
To test if the improvement is due to reduced production of Abeta, Hutter-Paier and Huttunen used a highly sensitive enzyme-linked immunosorbent assay to quantify the amount of soluble amyloid-beta being produced in the brain. They found that the peptides were reduced by more than 30 percent in the transgenic animals as compared to controls.
Exactly how the ACAT inhibitor reduces Abeta production is not clear, but a link between cholesterol and Alzheimer's disease has been known for some years. Epidemiological evidence has indicated that high serum cholesterol increases one's risk for the disease, and there's also a strong genetic association. Those carrying a specific variant (apoE4) of the gene for apolipoprotein E, the major cholesterol transporter in the brain, have a statistically greater risk of developing the disease. Some studies suggest that proteolysis of APP, which releases amyloid peptides, may be sensitive to shifts in distribution of the lipid. "We believe that there may be a cholesterol-sensitive interaction between APP and another protein," explained Kovacs.
Cognitive Improvement
Of course the gold standard for any Alzheimer's drug is that it can stop, or at least slow down, the memory losses and cognitive deterioration that everyone so fears. In mice, cognitive ability is often measured using the Morris water maze--a water tank with a hidden platform. Not liking water very much, mice quickly learn to find the platform and climb to safety. Transgenic mice that overexpress mutant APP are known to perform poorly, taking longer to find sanctuary than normal mice do. But would the drug help?
Dora Kovacs, Henri Huttunen, and colleagues have found that inhibiting esterification of cholesterol prevents the deposition of amyloid-beta peptides in transgenic mice. (Photo by Graham Ramsay)
It did. Transgenic mice receiving the drug consistently performed better than mice on a placebo. At a little more than six months old, and having been on the drug for 54 days, mice took an average of about 42 seconds to find the platform. After three days of training, they improved to about 25 seconds, whereas mice on placebo were taking about 32 seconds. Though this trend was consistent, the results were not statistically significant. "This is most likely due to the fact that these animals are still quite young and have relatively little plaque burden," said Kovacs. She found support for this reasoning when she reanalyzed the data only for the female mice--which have greater amyloid deposition than their male littermates--since the results were statistically meaningful. After three days of testing, female mice on a placebo were taking more than 40 seconds to find the platform while those on the drug were taking about 15 seconds, on a par with the performance of normal mice.
Kovacs's lab is now extending these experiments to examine the effect of CP-113,818 on older animals. She is also testing another ACAT inhibitor, avasimibe. Because this drug has already been through phase III clinical trials for treatment of atherosclerosis and is considered safe for use in humans, it could be put on the fast track toward approval for Alzheimer's disease.
--Tom Fagan