New target for Alzheimer's disease

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.

“All the results together gave us idea that yes, alpha-7 is in part a mediator of the synaptic and cognitive pathology produced by beta amyloid accumulation,” says first author Gustavo Dziewczapolski, Ph.D., a postdoctoral researcher in Heinemann’s lab.

The findings also suggest that researchers seeking therapeutic targets for Alzheimer’s may be more successful if they block the function of the alpha-7 receptor or block beta amyloid’s access to alpha-7 rather than try to activate the receptor.

Dziewczapolski and Heinemann plan to continue their investigations of the alpha -7/beta amyloid connection, with the hope of identifying the mechanism behind the relationship and determining why the synapses die in Alzheimer’s.

“An Alzheimer’s epidemic is threatening to swamp the medical system within 20 years, but all clinical trials for targets that the field has identified have failed because of side effects or because they don’t work,” says Heinemann. “This is a completely different target.”

This work was supported in part by National Institutes of Health/National Institute of Aging, the Bundy Foundation, and the Ellison Medical Foundation.