In an article in the March 2, 2006, issue of Neuron, Dr. Frank LaFerla of the University of California, Irvine and his colleagues reported the first in vivo studies of the drug's effects. AF267B was developed by coauthor Abraham Fisher to activate particular receptors for the neurotransmitter acetylcholine. These specific receptors, called M1 receptors, are abundant in areas of the brain--the cortex and hippocampus--known to develop severe deposits of plaques and tangles in AD patients. Dysfunction in acetylcholine receptors has been shown to be characteristic of early stages of AD.
Receptors are proteins on the neuronal surface that are triggered by the chemical signals called neurotransmitters. This triggering initiates such cellular responses as the wave of electrical excitation of a nerve impulse.
As an animal model of AD, the researchers used a "triple knockout" mouse in which three key genes involved in normal brain protein processing pathways had been knocked out, creating both amyloid plaques and neurofibrillary tangles.
In their experiments, the researchers gave the knockout mice eight weeks of daily doses of AF267B and tested the animals' learning and memory abilities. One test involved measuring how well the treated animals could learn to find a submerged platform in a tank of murky water. This test is known to depend on the function of the hippocampus. The researchers found that the treated mice performed significantly better than untreated knockout mice on the task.
Significantly, found the researchers, the poorer performance of the untreated mice resulted from their relative inability to remember from day-to-day the location of the platform.
In another memory test, however, the treated mice did not show improved performance compared to untreated mice. In this test--which depends on the function of another Alzheimer's-affected brain region called the amygdala--the mice were required to learn to associate a dark chamber with an unpleasant shock.
Analyzing the brain tissue of the untreated and treated mice, the researchers found that treatment with AF267B reduced levels of both pathological plaques and tangles in the cortex and hippocampus, but not in the amygdala.
In experiments that demonstrated the central role of M1 receptors in AD-like pathology, the researchers also tested the effects on the mice of another drug, dicyclomine, that blocks M1 receptors. They found that both normal and knockout mice treated with the drug showed the characteristic learning and memory impairments, as well as amyloid and tangle pathologies.
The researchers also studied the effects of AF267B treatment on key enzymes involved in amyloid protein processing in the cell. They found evidence that the drug appears to work by affecting levels of these enzymes, as a result of its enhancement of M1 receptor activity.
The researchers concluded that "the results of the present study show the remarkable therapeutic potential of AF267B in attenuating the major hallmark neuropathological lesions relevant to AD and in restoring cognitive function, at least for certain tasks." They also pointed out the importance of the finding that administering dicyclomine to block M1 receptors exacerbated the disease pathologies.
"Further work, including clinical trials in humans, will be necessary to determine if this new generation of M1 agonists will produce a similar therapeutic efficacy as was observed in the [knockout] mice," they concluded.
The researchers include Antonella Caccamo, Salvatore Oddo, Lauren M. Billings, Kim N. Green, Hilda Martinez-Coria, and Frank M. LaFerla of the University of California, Irvine in Irvine, California; Abraham Fisher of the Israel Institute for Biological Research in Ness-Ziona, Israel. This work was supported by a grant to F.M.L. from the NIA (AG0212982) and the Alzheimer's Association (IIRG-02-3767).
Caccamo et al.: "M1 Receptors Play a Central Role in Modulating AD-like Pathology in Transgenic Mice." Publishing in Neuron 49, 671–682, March 2, 2006. DOI 10.1016/j.neuron.2006.01.020 www.neuron.org
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