For close to a decade, pharmaceutical researchers have been in hot pursuit of compounds to activate a key nicotine receptor that plays a role in cognitive processes. Triggering it, they hope, might prevent or even reverse the devastation wrought by Alzheimer’s disease.
A new study from the Salk Institute for Biological Studies, however, suggests that when the receptor, alpha-7, encounters beta amyloid, the toxic protein found in the disease’s hallmark plaques, the two may actually go rogue. In combination, alpha-7 and beta amyloid appear to exacerbate Alzheimer’s symptoms, while eliminating alpha-7 seems to nullify beta amyloid’s harmful effects.
These findings, reported recently in The Journal of Neuroscience, may shed new light on the processes leading to Alzheimer’s and could have important implications for researchers seeking to combat the disease.
Intrigued by earlier studies showing that beta amyloid seemed particularly drawn to the alpha-7 nicotinic receptors, researchers in the lab of Stephen F. Heinemann, Ph.D., in the Salk Molecular Neurobiology Laboratory, sought to determine whether the alpha-7 receptors actually modulate the effects of beta amyloid in Alzheimer’s disease.
“Alpha-7 is expressed all over the brain,” says Heinemann, whose group first identified the brain receptors that respond to nicotine. “All mammals have it, and it’s probably essential for something, but we don’t know what.”
Hypothesizing that the alpha-7 nicotinic receptors mediate beta amyloid effects in Alzheimer’s disease, Heinemann’s team crossed mice engineered to lack the gene for alpha-7 with a mouse model for Alzheimer’s disease, which had been genetically engineered to overexpress amyloid precursor protein (APP), an antecedent to beta amyloid. They then put the offspring through a series of memory tests.
Surprisingly, those with both mutations—too much APP and no gene for alpha-7—performed as well as normal mice. The Alzheimer’s mice, however, which had the alpha-7 gene and also overexpressed APP, did poorly on the tests. Pathology studies revealed the presence of comparable amounts of plaques in the brains of both types of mice, but in those lacking the alpha-7 gene, they appeared to have no effect. Similar disparities were evident in measurements of the synaptic function underlying learning and memory.