When I read the news of a possible breakthrough in Alzheimer’s research, it sounded at least somewhat encouraging. Maybe, maybe someday it could lead to a cure or at least an effective treatment for this dreadful scourge of an illness:

The study, published in the Journal of Experimental Medicine on Wednesday, found that by removing the BACE-1 enzyme, the amyloid plaque in the brains of adult mice with Alzheimer’s disease not only stopped building up, but also dissolved away without negatively affecting their neuro-development.

“To our knowledge, this is the first observation of such a dramatic reversal of amyloid deposition in any study of Alzheimer’s disease mouse models,” senior researcher Riqiang Yan said in a press release.

The question almost immediately came to me: how on earth do they get mice with Alzheimer’s? Do mice get Alzheimer’s naturally? And how can the researchers tell that the mice have it—do the mice forget how to run the mazes, and just wander around aimlessly till they’re rescued?

I followed that link to the press release, and it addressed the issue a bit:

To investigate whether inhibiting BACE1 in adults might be less harmful, Riqiang Yan and colleagues generated mice that gradually lose this enzyme as they grow older…

The researchers then bred these rodents with mice that start to develop amyloid plaques and Alzheimer’s disease when they are 75 days old. The resulting offspring also formed plaques at this age, even though their BACE1 levels were approximately 50% lower than normal. Remarkably, however, the plaques began to disappear as the mice continued to age and lose BACE1 activity, until, at 10 months old, the mice had no plaques in their brains at all.

I’m assuming—although I didn’t see anything about this aspect—that the only way they can tell the extent of the brain plaques is to kill some of the mice and do autopsies.

So, how do you “generate” mice that lose the enzyme? Do you breed them for the trait the old-fashioned way, by selecting those that have it and end up with a strain composed of their offspring? Or is it more complex than that? And what of those mice with early-onset Alzheimer’s? How do they come about?

And how does all of this relate to the disease process of humans who get Alzheimer’s in the usual way?

According to this article, however, research with mice hasn’t always transferred to humans in the past. That’s hardly surprising, nor does it seem to be the fault of researchers.

I decided to Google the question of how scientists obtain the Alzheimer’s mice in the first place, and this explanation came up. I can’t say I totally understood it, but I believe I got the general gist of it. The mice are transgenic:

Transgenic modeling has been pursued on the basis of the amyloid hypothesis and has taken advantage of mutations in the amyloid precursor protein and the presenilins that cause familial forms of Alzheimer’s disease. Modeling has been most aggressively pursued in mice, for which the techniques of genetic modification are well developed. Transgenic mouse models now exist that mimic a range of Alzheimer’s disease”“related pathologies. Although none of the models fully replicates the human disease, the models have contributed significant insights into the pathophysiology of β-amyloid toxicity, particularly with respect to the effects of different β-amyloid species and the possible pathogenic role of β-amyloid oligomers. They have also been widely used in the preclinical testing of potential therapeutic modalities and have played a pivotal role in the development of immunotherapies for Alzheimer’s disease that are currently in clinical trials…

Regardless of the species chosen, transgenic technologies introduce genetic modifications. Therefore, successful modeling requires the disease to be associated with a genetic mutation or at least for a hypothesis to exist regarding the likely pathophysiology of the disorder that can be modeled by a genetic modification. To be useful as an animal model, the transgenic organism must also be able to exhibit the essential pathological, physiological, or behavioral features of the human disease.

AD may in many ways be regarded as the ideal disease for modeling in transgenic animals. First, it has a well-recognized pathology consisting of senile plaques and NFTs. The major constituents of these lesions are well defined, being the β-amyloid (Aβ) peptide in the case of plaques and hyperphosphorylated forms of tau in NFTs. AD also has other well-recognized pathological features, including neuronal and synaptic loss, dystrophic neurites, reactive astrocytes, and activated microglia. There is, in addition, a well-defined behavioral phenotype that can be modeled in the mouse…

Transgenic organisms are generated by 1 of 2 general strategies. In the first, a genetic modification is introduced on top of the existing genetic makeup of the organism. In the second, the homologous gene of interest is modified selectively in its normal chromosomal position; this process is called gene targeting. These strategies have been developed to different degrees in different organisms.

In mice, both approaches are highly developed.

There’s much much more at the link, if you’re interested.

[NOTE: This post also made me think of the Ursula LeGuin short story “Mazes” in her book of stories entitled The Compass Rose, which I highly recommend.]