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.