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October 6, 2011
Is Alzheimer's An Infectious Disease? The Spread of Protein Misfolding
That's what this paper in Molecular Psychiatry is suggesting. The authors injected material from human Alzheimer's patients into the brains of normal mice, and saw what appears to be the induction of amyloid pathlology. This didn't happen in control animals, got worse with time, and wasn't just noted at the point of injection. Their hypothesis is that Alzheimer's might be a prion-type disease of protein misfolding, and possibly capable of being spread by infectious particles. I recall ideas like this being advanced in the past, but this is the first time I've seen evidence like this (hasn't this sort of experiment been run before?) It's simultaneously fascinating and alarming, and I would very much like to see it repeated and confirmed.
This comes as broadly similar ideas are being advanced in Parkinson's disease, where recent work has shown misfolded alpha-synuclein protein (long known as a key factor) spreading slowly through infected neurons. No one has ever seen evidence of transmissible Parkinson's between humans, but it does seem to move between neurons like an internal epidemic.
And that comes as broadly similar ideas are being advanced in ALS. A recent paper in PNAS suggests that a mutant form of superoxide dismutase 1 (which had already been found to be associated with the disease) can be spread by the injection of precursor cells that express it. That makes you think that the SOD1 mutant (G93A, which is not the most common mutation in humans) may also have prion-like properties, and can induce other proteins to misfold along with it. What's especially interesting (and again, rather alarming) is that it apparently can recruit normal SOD1 into this state. (In this study, though, the effects were confined to the region around the introduction of the cells, so the spread was not that fast). It's important to note again that, as in the case of Parkinson's, no one has ever seen evidence that ALS is transmissible from person to person - in fact, I don't think that anyone has ever seen ALS in anyone without the mutation in their genome. But this does shed some light on what happens internally.
So taken together, the spreading-protein-misfolding mechanism seems to have a lot of momentum behind it. The big question is whether it can result in human-to-human transmission. Even in the cases where we've confirmed prion-based disease, transmission seems (fortunately) rather difficult, although this is a very active field of research, and definitely something to keep an eye on. The possible Alzheimer's connection is especially interesting, since that one is simultaneously more common and does not have a strong genetic component. It occurs (as far as we can tell) mostly sporadically. The amyloid hypothesis for its cause has been taking some hits in recent years, but the other side of the story is still very much alive. . .
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