Serotonin-Activated Kinase Can Fight Amyloid Plaques
The road to developing Alzheimer's drugs has been littered with disappointments. But this week, researchers from Washington University in St. Louis published data suggesting that another class of drugs may be useful in preventing the formation of amyloid plaques: antidepressants that work via selective serotonin reuptake inhibition (SSRI).
Both corresponding authors of the study, which appeared in the Aug. 23, 2011, online edition of the Proceedings of the National Academy of Sciences, took pains to point out that a cause-and-effect relationship between SSRIs and lower plaque burden has so far been established only in mice. In humans, "we don't have any data that SSRIs reduce plaques," first author John Cirrito told BioWorld Today. "It's not going to be a robust finding until we can show it in a person."
Still, clinical data showed an association of antidepressant treatment with lower plaque burden in humans, and mouse data provides a reasonable explanation about how one might lead to the other.
When senior author Yvette Sheline started looking at the relationship between depression and plaque burden, she was not expecting to find that depressed individuals had a lower plaque burden; quite the contrary.
Depression is a known risk factor for Alzheimer's disease, and so "initially, I hypothesized the opposite," she told BioWorld Today, namely, that depressed individuals would have a higher burden of amyloid plaques, which are the anatomical hallmarks of Alzheimer's.
But when she tested that idea in cognitively normal elderly adults, "to my dismay, I proved my hypothesis wrong." Depressed patients had a lower plaque burden, not a higher one.
In mulling over possible reasons, Sheline realized that one of the differences between depressed and nondepressed people is that some of the former will be treated with antidepressants.
"It seemed like an unlikely [reason]," she said. "But I thought, 'well, I might as well take a look.'"
And indeed, a lower plaque burden was seen only in depressed individuals who had been treated with SSRIs within the past five years. And the more SSRIs they had taken, the lower their plaque burden was.
The finding may have been intriguing, but it did not demonstrate cause and effect. Indeed, "there's no way to do that in humans," Sheline said.
So she and her colleagues looked at the effects of SSRI treatments in transgenic mice that express human presenilin, which are animal models for studying Alzheimer's disease.
They found that acute treatment with several SSRIs, including Prozac (fluoxetine, Eli Lilly and Co.) and Celexa (citalopram, Forest Laboratories Inc.) reduced levels of A-beta – the individual peptides that aggregate first into oligomers and, ultimately, amyloid plaques in the animals. Chronic treatment with Celexa also reduced levels of plaque.
The drug did not appear to work by affecting neuronal firing. Instead, the increased serotonin levels activated a kinase: extracellular signal-regulated kinase (Erk).
Erk, Cirrito said, is a "highly promiscuous" kinase. "It can be activated by probably dozens of extracellular molecules." Nevertheless, the effects of that activation are highly dependent on the level of other metabolites in the cell, and so Erk's effects end up being quite specific. When the team used another brain signaling molecule, brain-derived neurotrophic factor (BDNF), to activate ERK, that activation "had no effect on A-beta levels," Cirrito said.
A number of questions remain about whether increasing serotonin signling will have an effect on plaque formation, let alone cognitive function, in humans. The team is working on a prospective study to test whether SSRIs will do any good in humans.
On the animal side, the team plans to look at how SSRI treatment affects the levels of A-beta oligomers, intermediates between A-beta peptides and plaques that may well be more toxic than the plaques themselves. Although both A-beta monomers and plaque levels were lower in the treated mice, Cirrito said that "the way we measure Abeta would not detect oligomers in the ISF so we cannot make claims on those species one way or the other."
Given these uncertainties, "I absolutely don't want people running out and starting antidepressants" because they might reduce plaques, Sheline said. But if the approach does pan out, SSRIs could ultimately become a plaque-fighting weapon of choice.
"They are so gorgeously safe in humans," she said.
Published: August 24, 2011
Suite: 1100 | Atlanta, Georgia 30346, USA
In the U.S. and Canada: 1-800-477-6307
Outside the U.S.: 1-770-810-3144
In the U.S. and Canada: 1-800-336-4474
Outside the U.S.: 1-215-386-0100
Hours: Monday - Friday, 8:00am - 6:00 pm EST
Sign up for Highlights FREE e-mail newsletter