As mentioned yesterday, Alzheimer’s therapies have, for the most part, been a cliff over which people push bales of money. There are plenty of good reasons for this: we don’t really know what the cause of Alzheimer’s is, when you get down to it, and we’re the only animal that we know of that gets it. Mouse models of the disease would be extremely useful – you wouldn’t even have to know what the problem was to do some sort of phenotypic screen – but the transgenic mice used for these experiments clearly don’t recapitulate the human disease. The hope for the last 25 years or so has been that they’d be close enough to get somewhere, but look where we are.
A team from several Japanese universities has some suggestions about what might be going wrong in that part of the field. In 2014 a paper from these groups described a new model that knocked-in mutant forms of amyloid precursor protein (APP), as seen in some of the human early-onset forms of the disease. (That’s as opposed to overexpression of APP and/or presenilin proteins themselves). This new paper says that the pathology seen in the previous rodents is not actually due to the amyloid protein that they’ve been engineered to overexpress.
One of the supposed markers of amyloid toxicity is the production of the p25 protein, an activator of the CDK5 enzyme. There was a lot of interest a few years ago about reports of this in human brain tissue, post-mortem, but the field has been rather confused since then, with some labs saying that this was indeed a good market in both mouse models and humans, and others unable to reproduce the effects. p25 is elevated, though, in the APP-overexpressing mice, which has kept interest alive in the connection between the two. It appears, though, that the p25 in these mice is a function of membrane disruption caused by the protein overexpression. The single-APP-knock-in mice, they report, have tons of amyloid, but no p25 to speak of.
In fact, they say, most of the phenotypes that you see in the APP/presenilin-overexpressing mouse model are probably artifacts. As you would figure, some others in the field are not taking that suggestion very well – here’s an excellent roundup from Alzforum on the situation as it stands now. The Japanese single-knock-in mice were very difficult to generate, are much in demand, and haven’t quite been around long enough to see what happens to them as they age. They might be just what the field has been looking for, or they might turn out to be another dead end. But either way, they seem to be pointing out serious problems with the previous standard mouse models, which would call into question the relevance of hundreds (thousands?) of previous papers using them.