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Alzheimer’s and Antimicrobial Amyloid

A recent paper in PLoS suggests a new function for beta-amyloid, the bulky protein that clumps together to form the plaques riddling the brains of people with Alzheimer’s disease. Conventional wisdom had always been that the protein was pure junk. But prominent Harvard researchers Rudolph Tanzi and Robert Moir have offered data to suggest beta-amyloid is an antimicrobial peptide, meaning it could be called into duty when the brain encounters a serious infection.

Given that the NYTimes coverage of the paper was one of the most emailed stories last week (and as a teaser for our April 5 cover story about Alzheimer’s drugs in development), it seemed worth taking a quick look at the significance of the results.

First, why does this new research matter? Well, if it turns out that beta-amyloid serves a protective function, it could put billions of dollars of big pharma’s drug development money on the line. Nearly every drug being tested in patients with Alzheimer’s somehow touches on beta-amyloid—either by sequestering the protein (Pfizer/J&J/Elan’s bapineuzumab, in Phase III trials) or blocking a key enzyme in the production of the protein (for example Lilly’s semagacestat, in Phase III trials, and Bristol-Myers Squibb’s BMS-708163, expected to move into Phase III at the end of this year). In other words, nearly all of big pharma’s eggs are in the beta-amyloid basket.

But what do the results really mean? Although there is still a lot of research to be done to fully understand the exact nature of the antimicrobial function, Harvard’s Moir offered a few theories. “The first thing it does is broaden the horizons for potential drug targets,” Moir says. If it beta-amyloid is indeed an antimicrobial peptide, then the question is why levels of it are rising in Alzheimer’s patients. The peptide could be serving a function in the brain, for example keeping a low-level chronic infection under control, he says. “Maybe it is going up for good reason, and getting rid of it completely may not be the best idea.”

Moir points out that in the infamous Phase II study of an immunotherapy to lower levels beta-amyloid, Elan’s AN1792, the trial had to be halted because a portion of the patients given the drug developed brain infections.

The second possibility is that the brain is exposed to a transient infection that causes the immune system to switch on a response—in this case, beta-amyloid production—that never gets switched off. Many think autoimmune diseases like multiple sclerosis could be triggered by such an event.

In the last scenario, the overproduction of beta-amyloid could be a result of what has long been assumed in Alzheimer’s disease—that something went wrong in the genetic blueprint and caused the abeta-making machinery to go awry.

Still, Alzheimer’s experts are cautious about reading too much into these early results. There’s certainly enough science to support beta-amyloid having some antimicrobial activity, says Sam Gandy, associate director of the Mount Sinai Alzheimer’s Disease Research Center in New York. “The question is whether its relevant,” he says. “I think it would be intriguing to test some of the implications of Rudy’s work in mouse models now.” For example, Gandy thinks it would be interesting to see if mice inoculated with abeta would be more susceptible to meningitis.

“But without that next step…I can’t really make the leap to humans to say this is obviously a part of the antimicrobial defense system,” Gandy says.


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    Apr 1st 201015:04
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    [...] accurate antimicrobial choices. Equally important are drug resistance and sensitivity data for …Alzheimer's and Antimicrobial Amyloid | The HaystackA recent paper in PLoS suggests a new function for beta-amyloid, the bulky protein that clumps [...]

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