Stem Cells as Culprits in Alzheimer's Disease

Previously, we used the “Match Studies” app to search for knockouts, drugs, whatever that mimic or counter the Alzheimer’s transcriptomic fingerprint. We could use the app because our own canonical Alzheimer’s signatures, as well as the signatures in Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets, contained both upregulated and downregulated sets. Many datasets do not contain both. For example, cell-type clustering sets usually do not contain upregulated and downregulated portions. They may simply contain “cluster 1”, “cluster 2”, “cluster 3”, etc.

Here, we wish to look at Alzheimer’s disease from the point of view of cell types that may either be predominant or depleted. Again, a caveat under which we proceed is that fact the our canonical Alzheimer’s sets are derived from multiple studies that examined a variety of brain regions. However, we’ll also look at the five clusters described in the previous post, which focus entirely on the parahippocampal gyrus (PHG).

First, we grab a set that is upregulated in Alzheimer’s…our “canonical” set (dbase ID 123049121). We paste the ID into the “Fisher” app, select “cell type” for “Experiment/Data Type”, and “Brain” under “Cell Type”, and submit. We then examine the output, and proceed with entry of 11 more datasets (the canonically downregulated set and the five PHG signatures, both of which have up- and downregulated portions). Below, in a crude form, is what we found:

Dataset	Cell Types that Mimic the Dataset
Canonically up in Alzheimer’s	upregulated in glioblastoma stem-cell like tissue (GSCs) vs GSC culture-spheres, human embryo ventral midbrain radial glia IIa cluster, 60% human embryo ventral midbrain pericyte cluster, mouse astrocyte cluster 3
Canonically down in Alzheimer’s	human embryo ventral midbrain serotonergic cluster, human embryo ventral midbrain dopaminergic 2 cluster, human embryo ventral midbrain dopaminergic 1 cluster, human embryo ventral midbrain NBgabaergic cluster, fetal retina cluster 8
Up in Signature A	mouse olfactory bulb neuron cluster 7, human embryo ventral midbrain dopaminergic 2 cluster, dominant (at least 95% of all counts) in microglia "ambiguous" cluster 13, human embryo ventral midbrain serotonergic cluster
Down in Signature A	fetal retina cluster 11 (fibroblast)
Up in Signature B1	Nothing of significance
Down in Signature B1	upregulated in adult nscs vs glioma nscs, dominant (at least 50% of all counts) in microglia cluster 10, upregulated in glioblastoma stem-cell like tissue (GSCs) vs GSC culture-spheres
Up in Signature B2	Nothing of significance
Down in Signature B2	upregulated in adult nscs vs glioma nscs
Up in Signature C1	astrocytes cluster 4, upregulated in glioblastoma stem-cell like tissue (GSCs) vs GSC culture-spheres, mouse astrocyte module "lightcyan"
Down in Signature C1	mouse olfactory bulb neuron cluster 7
Up in Signature C2	astrocytes cluster 4
Down in Signature C2	human embryo ventral midbrain serotonergic cluster, human embryo ventral midbrain mature neuron cluster, human embryo ventral midbrain dopaminergic 1 cluster

Results that appear more than once are colored. Pardon the gaudiness. As always, if you want the finer details (p-values, study names/IDs, etc), you can go through the exercise yourself. It doesn’t take long. Some of the above studies overlap quite significantly with the Alzheimer’s sets, with P-values as high as 10^-25.

Here’s our prime observation: it’s all about stem and embryonic cells. We have plenty of studies involving adult brain tissues, but none of these came to the fore. Thus we see results involving upregulation in stem cells vs. more mature cells, multiple embryonic brain clusters, and adult neural stem cells vs. glioma stem cells. Note that the olfactory bulb (along with the subventricular zone of the brain) is a hotbed for neural stem cells (NSCs). Note also that some of the knockouts/mutations mentioned in our previous post as mimicking/countering Alzheimer's would appear relevant to stem cell biology...arx, hoxa5, sufu, etc.

Unfortunately, as might be expected given the opposing five signatures in Molecular subtyping of Alzheimer’s disease, it’s unlikely that there’s an NSC enriching/depleting strategy for all forms of Alzheimer’s. For example, the serotonergic cluster that is downregulated in both our canonical set and signature C2 is upregulated in signature A.

A quick Google Scholar search reveals a myriad of studies/reviews relating to stem cell therapy for neurodegeneration, but a paucity of works suggesting stem cells as culprits. Given the low abundances of these cell types and the necessity of working with post-mortem human brains, it’s not the easiest sort of study to conduct. Here’s a review that does offer a perspective and relevant citations: Adult Hippocampal Neurogenesis in Major Depressive Disorder and Alzheimer’s Disease.

To be clear, the above data doesn't absolutely point a finger at brain stem cells. After all, there aren't many of them kicking around in the brain, let alone the aged brain. More likely, we're looking at a signature that is associated with stem cells, spread over more abundant classes of cells. Actual stem cells could be playing a role in initiation of these signatures. 

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