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Researchers Identify First Compound To Block Progression Of Alzheimer's Disease

March 5, 2006
University of California - Irvine
Researchers at UC Irvine have found that a new compound not only relieves the cognitive symptoms of Alzheimer's disease, but also reduces the two types of brain lesions that are hallmarks of this devastating disease, thereby blocking its progression.

Researchers at UC Irvine have found that a new compound not only relieves the cognitive symptoms of Alzheimer's disease, but also reduces the two types of brain lesions that are hallmarks of this devastating disease, thereby blocking its progression.

In a study with genetically modified mice, a team of UCI researchers led by Frank LaFerla, professor of neurobiology and behavior, found that a compound known as AF267B, developed by paper co-author Abraham Fisher of the Israel Institute for Biological Research, reduced both plaque lesions and tangles in brain regions associated with learning and memory. Although drugs exist on the market today to treat the symptoms of Alzheimer's, AF267B represents the first disease-modifying compound, meaning it appears to affect the underlying cause and reduces the two signature lesions, plaques and tangles.

The researchers report their findings in the March 2 issue of Neuron.

"AF267B could be a tremendous step forward in the treatment of Alzheimer's disease," said LaFerla, who serves as co-director of the UCI Institute for Brain Aging and Dementia. "Not only does it appear to work on the pathology of Alzheimer's and ease its symptoms, it crosses the blood-brain barrier, which means it does not have to be directly administered to the brain, a significant advantage for a pharmaceutical product. Although we cannot determine what the effects of AF267B will be in humans until clinical trials are complete, we are very excited by the results our study has yielded."

According to LaFerla, AF267B works by mimicking the effects of the neurotransmitter acetylcholine, a chemical in the brain essential for learning and memory. Neurotransmitters act as carriers for messages between brain cells and bind to receptors on the cells' surfaces. Acetylcholine generally binds to specific receptors in the brain, including the M1 receptor, a potentially novel therapeutic target for Alzheimer's disease.

Scientists have known for years that there is a major loss of the neurons that produce acetylcholine in the brains of Alzheimer's patients. Compounds classified as M1 agonists -- meaning that they mimic the effects of acetylcholine and bind to M1 receptors -- are regarded as one hope for counteracting or compensating for the loss of acetylcholine. Unfortunately, previous M1 agonists had been tested but failed in clinical trials.

AF267B, however, appears to have overcome the problems seen with earlier generations of M1 agonists. In this study, the researchers found that the administration of AF267B reduced the amount of plaques and tangles in the hippocampus and the cortex of the mice, and improved cognitive performance. When the compound binds to the M1 receptor in those regions of the brain, the levels of an enzyme known as alpha secretase are increased. This enzyme prevents the production of beta-amyloid, which, according to a theory known as the amyloid cascade hypothesis, also would block the eventual accumulation of tangles.

"These findings are highly important because they offer a new understanding of the importance of cholinergic activation of cells in the hippocampus and cerebral cortex that are essential for creating and preserving memories," said James L. McGaugh, research professor of neurobiology and behavior and a member of the National Academy of Sciences who pioneered the study of drug and stress-hormone influences on memory. "The evidence suggests the exciting prospect of possibly preventing the development of this devastating disease."

TorreyPines Therapeutics, a biopharmaceutical company in San Diego, is conducting clinical studies to determine whether the compound is safe for use. In early tests, the compound was well tolerated at tested doses in a group of young, healthy males. Alzheimer's disease is marked by the accumulation of two types of brain lesions -- beta-amyloid plaques and neurofibrillary tangles. The disease is a progressive neurodegenerative disorder, affecting 4.5 million to 5 million adults in the United States. If no effective therapies are developed, it is estimated that 13 million Americans will be afflicted with the disease by 2050. It is the third most expensive disease to treat and the third leading cause of death, behind cancer and coronary heart disease.

In recent years, LaFerla has been at the forefront of Alzheimer's research and has made a number of significant strides in understanding the molecular development of the disease. In addition to finding that early treatment of beta-amyloid plaques can halt the progression of Alzheimer's, he and other members of his research team created the genetically-altered mouse that was used in this study. His work also determined that chronic nicotine exposure worsens some Alzheimer-related brain abnormalities, contradicting the common belief that nicotine can actually be used to treat the disease.

This study was funded primarily by a grant from the National Institute on Aging and the Alzheimer's Association.

About the Study: LaFerla and his associates, including the study's first author Antonella Caccamo, a UCI staff research associate, tested AF267B on both normal mice and on special Alzheimer's mice engineered by the LaFerla lab, which manifest several features of Alzheimer's including plaques and tangles. The mice were injected with AF267B or with a compound called dicyclomine, which is an M1 antagonist and performs exactly the opposite function of an M1 agonist. Dicyclomine was used as proof of concept; if M1 agonists help improve cognitive function and reverse memory decline, then an M1 antagonist should have the opposite effect.

After eight weeks of daily AF267B administration and four weeks of daily dicyclomine injections, the mice were tested using two different behavioral tasks. In the Morris water maze, mice are tested for spatial reference, a task dependent on the hippocampus and the cortex. In the test, the mice were placed in a maze in a water tank and encouraged repeatedly to locate a hidden platform in the tank by making spatial association in the room to facilitate their search. After the platform was removed, the researchers monitored in subsequent trials how many times the mice would cross over the space where the platform used to be -- an indication of how well they remembered its location.

Although AF267B had no effect on the normal mice who were not afflicted with the plaques or tangles, the tests clearly showed that the Alzheimer's transgenic mice treated with this compound better remembered the platform's location compared to the control group of transgenic mice that received placebo. Strikingly, all the mice, both normal and transgenic, did not remember the platform's location when injected with dicyclomine, proving that an M1 antagonist does seem to have an adverse effect on memory. Neuropathological examination of the mice also showed that there were fewer plaques and tangles in the brains of the transgenic mice treated with AF267B than in the brains of the transgenic mice that received placebo. All the mice injected with dicyclomine showed more diffuse plaques and tangles.

LaFerla and his team also used a test related to contextual information and unpleasant stimuli, memories processed by the amygdala. The mice were placed inside a dark box to familiarize themselves with that context. After a few seconds, a light went on and a door was opened to a second, darker compartment. As mice prefer to stay in the dark, they moved to the dark compartment where they were given a mild foot shock. At a later time, the mice were replaced in the starting compartment and tested to see how long they would avoid the dark, shock-associated compartment, a sign of whether they remembered the unpleasant stimulus.

Whereas the normal mice avoided the shock compartment, all the Alzheimer's mice, including those that had been treated with AF267B, showed impaired memory for this task. A neuropathological examination of their brains showed no reduction of the plaques or tangles in the amygdala. However, the administration of dicyclomine reduced memory function in both normal and transgenic mice.

According to LaFerla, this is because in the amygdala there is less production of the alpha secretase enzyme, which when active prevents the formation of beta-amyloid. Thus, the levels of this enzyme could not be increased by AF267B in the amygdala and the production of beta-amyloid could not be prevented.

LaFerla's research has shown previously that the accumulation of beta-amyloid within neurons is the trigger for the onset of memory decline in Alzheimer's. His team also has shown that removing plaques from the brain can lead to a clearance of the tangle pathology, supporting a theory known as the "amyloid cascade hypothesis." According to this hypothesis, it is the buildup of beta-amyloid in the brain that triggers the development of Alzheimer's in people.

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Materials provided by University of California - Irvine. Note: Content may be edited for style and length.

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University of California - Irvine. "Researchers Identify First Compound To Block Progression Of Alzheimer's Disease." ScienceDaily. ScienceDaily, 5 March 2006. <>.
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