A new drug that enhances the activity of a key brain cell receptor involved in Alzheimer's disease (AD) reverses learning and memory deficits in mice engineered to have pathological hallmarks of the disease. What's more, the drug, called AF267B, reduces both of the pathologies-the brain-clogging buildup of protein "amyloid plaque" outside brain cells and the protein "neurofibrillary tangles" inside the cells.
In an article in 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.