Here's a recent review of the state of the field of Alzheimer's research in non-humans. To summarize...these studies, nearly all of which seek to induce amyloid or tau pathology, have a dismal record.
The WIMG database has quite a large compendium of Alzheimer's studies...the term "Alzheimer's" is found in about 1200 lists, comprised primarily of human and mouse studies. Previously, we used the human portion of these lists to construct new lists of genes that are canonically up- and down-regulated in the Alzheimer's disease brain (dbase IDs 123049121 and 123050121). How do mouse studies match up with these two lists?
Knowing that it's hard to get any perturbation to generate a result that looks like our Alzheimer's upregulation list, let's start with transcripts that are canonically down-regulated in Alzheimer's. Not surprisingly, the studies that best match up with this list are the human studies that compose the list. This is followed by other human neural disorders...Creutzfeldt-Jakob, Nasu-Hakola, etc. The first mouse match is ranked 21st in terms of match significance (log(P) = -33). We've labeled it as transcripts "upregulated in mouse cortex 4d vs 2d after skull injury", but you can impose a double negative on that wording to get an equivalent: transcripts downregulated in mouse cortex 2d vs 4d after skull injury. Perhaps that wording makes it more obvious that we're talking about transcripts that are downregulated early in the process of injury recovery. These injury-related studies, in fact, dominate the top of our list of mouse studies that mimic the genes that are downregulated in Alzheimer's...of mouse studies, ranks 1, 3, 8 (spinal tissue!), and 10 (cerebral artery occlusion) match our Alzheimer's list fairly significantly.
How about rank 2? Here we're talking about a single-cell cluster ("neurons2") of brain stem neurons with and without a SOD1 mutation (Single-cell RNA-seq analysis of the brainstem of mutant SOD1 mice reveals perturbed cell types and pathways of amyotrophic lateral sclerosis). This is another theme of our mouse Alzheimer's-mimic list: clustering and/or cell-type results involving neurons, perhaps suggesting that very specific types of neurons may be more or less involved in Alzheimer's.
Another theme involves studies of embryonic brain cells. This is seen in ranks 5, 16, 18,19, and 21.
Studies that might seem rather odd in their ability to deliver an Alzheimer's signature involve genes downregulated in the colon (!) upon gavaging with mulberry extract nanoparticles (rank 4, GSE185351), genes upregulated on pyk2 knockout (27, GSE180598), genes upregulated in aorta on rage knockout (28, GSE15729), and genes downregulated in microglia on ehmt1 haploinsufficiency (36, Derepression of inflammation-related genes link to microglia activation and neural maturation defect in a mouse model of Kleefstra syndrome).
Wait a second...where are the explicit mouse Alzheimer's studies that involve, say, the 3XTG or 5XFAD models? Well, the first hint of such a result is found at rank 13: "genes negatively correlated w/plaque intensity in E4 5XFAD mouse brain". Note, however, that this doesn't quite fit the bill, as both the test and control samples involve a 5XFAD mouse brain. It turns out you have to go down to the 99th mouse study on our list to find such a result ("downregulated in mouse 5XFAD vs wt 8m hippocampus", GSE149243, log(P)=-11). In the process, you pass through studies involving the retina, muscles, adrenal glands, heart, myoblasts, and more. In other words, a myriad of seemingly irrelevant mouse studies do a much better job of mirroring the Alzheimer's signature than studies explicitly designed to generate the signature in a mouse brain.
At this point, if we had to say something positive about mouse Alzheimer's studies, we'd say that the 5XFAD model appears best. The first appearance of the term "APP/PS1" appears at rank 798. The term "3XTG" first appears at rank 1950 of 149,000 lists, with an unadjusted log(P) of -1.26.
Perhaps the mouse models do a better job of mimicking genes that are upregulated, not downregulated, in Alzheimer's. Let take a look. Here, the first mouse study is found at rank 45 with log(P)= -8: "up-regulated in mouse cortical culture on ursodiol" (GSE110256). Ursodiol, interestingly, is a bile acid generated by humans, but in higher concentrations in bears and hibernating animals. Perhaps there is some natural justice dealt out to the humans who torture bears for their bile juice.
Eliminating all non-mouse studies, study #2 involves downregulation of hypothalamus genes upon DHA treatment (GSE64807). We've previously noted the possible benefits of DHA. Again, we see studies involving injury: ranks 9, 11, 27 (a heart infarction study), and 53 (a skin-wounding study). Bearing in mind that the p-values aren't impressive, we also see a number of gene perturbation studies that parallel the upregulation signature: lsd1 knockout, hiv-gp120 overexpression, circSCMH1 overexpression, and arx mutation.
Where do we see the first occurrences of "5XFAD" or "3XTG"? Amazingly, the first explicit 5XFAD study is ranked #4273 (unadjusted log(P) = -0.76). The situation is worse for the first 3XTG study in the list: rank #5965; here, genes upregulated in the mouse model match our list of genes downregulated in Alzheimer's better than our list of upregulated genes.
Simply put, mouse Alzheimer's studies suck. Mouse studies that do mirror the Alzheimer's signature weren't conducted with the intention of furthering understanding of Alzheimer's. One could complain that we're judging the mouse studies based on a single perspective (gene set analysis of human vs mouse transcriptomes)...but, as seen in the aforementioned review, the mouse studies have failed in numerous other respects.
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If you're interested in perusing the full list of studies mentioned above, it's easy. Just go to the WIMG website, choose the Fisher tool, enter the database ID for either the Alzheimer's upregulation or downregulation list, and submit. To focus entirely on mouse studies, choose "Mouse" in the species box.
