. Alzheimer’s patient brain myeloid cells exhibit enhanced aging and unique transcriptional activation. bioRxiv. April 19, 2019

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  1. We have DAM, BAM, PAM, and now HAM (Human Alzheimer’s Microglia/Myeloid cells signature) to help us better understand how microglia change with disease.

    Srinivasan et al. used a novel method to isolate various cell types from frozen brain tissue, where they successfully isolated RNA from about half of the CD11b+ samples. The beauty of this method is that it does not require fresh tissue to capture the microglia signature as our method using viable microglia does. This allows the authors to carefully select annotated samples from the Banner Sun Health Research Institute Brain and Body Donation Program.

    However, the concern is that there might be a biological connection to the large number of samples that failed. This could be ruled out by comparing the finding to transcriptomics from microglia-specific nuclei from the same subjects, which would be a very informative comparison as the field of nuclei transcriptomics explodes. 

    Interestingly, Srinivasan et al. did not find the mouse DAM phenotype enriched in their human microglia from Alzheimer’s patients. Rather, half of their signature appeared to resemble more of an enhanced aging phenotype rather than cell activation as in the DAM phenotype.

    Only APOE was found both in the DAM and HAM signatures. We had also found APOE upregulated in our human aged microglia profile (HuMi_Aged) of aged individuals, who all had some degree of Alzheimer’s pathology if not a clinical diagnosis.

    Importantly, Srinivasan et al. found that it is possible for human microglia to have a DAM phenotype, but it is not seen in the human microglia from Alzheimer’s disease patients. This will have big implications as we work toward targeting microglia therapeutically. The caveat to this work is the small sample size, but it is an important beginning.

  2. It is exciting to see all these studies examining cell-type-specific responses to Alzheimer’s disease pathology at the transcriptomic levels. The isolated cell-type approach from Srinivasan, Friedman et al. and the single-nucleus approach from Mathys, Davila-Velderrain et al. shared some common findings that challenge whether microglial phenotypes described in mouse models of neurodegeneration exist in human disease. Although both studies identified upregulation of APOE in microglia from AD brain, other “disease-associated microglia” (DAM) markers were not as readily detectable.

    It is worth noting that DAM cells as described by Keren-Shaul et al. comprised a relatively small proportion of microglia in the 5xFAD amyloid model, which may make it difficult to capture with single-cell/nucleus analysis (Keren-Shaul et al., 2017). In this regard, it would be interesting to use the cell-extraction approach described by Srinivasan et al; using putative DAM markers such as CD11c would enrich for microglia in DAM-like transcriptomic states.

    Additionally, the SlideSeq approach recently described by Rodriques, Stickels et al. would be a powerful way to get around the difficulty in enriching for particular cell types such as microglia or astrocytes and assess the transcriptomic state of cells in regards to their spatial proximity to pathology (Rodriques et al., 2019). 

    References:

    . A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.

    . Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution. Science. 2019 Mar 29;363(6434):1463-1467. Epub 2019 Mar 28 PubMed.

    View all comments by Jason Ulrich

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