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March 16, 2010
Beta-Amyloid: An Antibiotic?
Now here's something that I don't think anyone expected. A recent paper in PLoS One makes the case that beta-amyloid, the protein that has been fingered for decades as a major player in Alzheimer's disease, is actually part of the body's antimicrobial defenses.
Well, it's good to hear that it's doing something. Many people had hypothesized that it was a useless (indeed, harmful) byproduct, a waste stream from aberrant processing of the amyloid precursor protein (APP). Still, there have been reports over the years that beta-amyloid was substrate for active transport pumps, might be a ligand for various receptors, etc., but not everyone was willing to take these results seriously.
But it turns out that some of A-beta's properties are similar to those of innate host defense peptides. When this latest team checked the amyloid protein's activity, it turns out to be pretty active. The prototype peptide in this area, LL-37, appears to have a broader spectrum of activity, but A-beta beats it against several organisms, most notably the yeast C. albicans. And as it turns out, brain homogenates from Alzheimer's patients are much more active against yeast in vitro than samples from age-matched controls without the disease. But that only holds true for parts of the brain (like the temporal lobe) that are known to be high in amyloid. Samples from the cerebellum (which doesn't usually show Alzheimer's pathology) had no activity. (One has to wonder if this is the first time - or at least the first time in a very long while - that anyone's evaluated human brain homogenates for their microbicidal activity).
This could lead to a complete rethink of Alzheimer's pathology. It's been known for a long time that there's a big inflammation component to the disease - perhaps the problem (or at least the trigger) is an underlying infection that sets off the innate immune system in the brain. Larger than normal amounts of beta-amyloid are produced in response, but it starts to precipitate out.
The more familiar adaptive immune system has limited access to the CNS, although that's not stopping people from trying to use it. But that approach (and many others) presume that beta-amyloid is a cause of the disease. Perhaps it isn't. Maybe it's the body's attempt at a solution - and if that's true, we need to look elsewhere for the cause, and soon. This is one of the most thought-provoking looks at Alzheimer's that I've seen in a long time. Here's hoping it leads to something new.
Update: here are some more comments on this paper, and here are some speculations about amyloid as a protective agent.
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