. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. Nat Med. 2020 Jan;26(1):131-142. Epub 2020 Jan 13 PubMed. Correction.


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  1. This study from Yingyue Zhou from the Colonna lab is exactly the sort of study that the field should be doing more of—comparing actual human transcriptomic analyses with those from animal models is the key to determining which cell types (or subtypes of cells) we are effectively able to model in a disease state in rodents. There are so many different AD models available to researchers, with more being produced each year, but researchers need to remember that not all models are equally appropriate for studying any one particular cell, pathway, or state of disease. This comparison of human and 5XFAD mouse cells is important, and something that should be done more often. We need to have a more comprehensive understanding of the subsets of disease-associated cells (e.g., microglia, astrocytes, etc.) that are properly recapitulated in current animal models. When we find a subset that is similar, we should study it, but if we do not find similarities we should not despair, but instead look for more appropriate models. Human responses must be the gold standard for studying disease-relevant functional deficits.

    Two things struck me in particular that will no doubt spark much discussion and further investigation:

    1. It was surprising, after making such a biologically important comparison, how the discussion of C4b+Serpina3n+ oligodendrocytes was conducted … "In the 5XFAD model, oligodendrocytes adopted a reactive signature including C4b and Serpina3n that was not evident in human AD samples." To me this highlights a point that the field must start to take notice of and address together. If a phenotype/subtype/transcriptomic signature is not present in human patients, is it a viable discovery for future investigation into the disease? What do we do now with the knowledge of a rodent-specific response? Is this a response that does not occur in human patients, or is this subtype functionally similar to one in humans, but with different markers and mechanisms of activation?

    2. "Neuronal loss in AD may dampen the need for astrocytic scavenger functions devoted to disposal of neuronal toxic waste. In parallel, astrocytes upregulated a signature indicative of extracellular matrix protein synthesis related to glial scarring." Again this is an interesting finding—and the biological implications are likely to open up a new avenue of investigation. It highlights that changes in one cell type may not necessarily mean these cells are reactive in a way that is driving disease pathology, but instead may simply be responding to the changing metabolic needs of the cells around them. An alternative reason for this may be that the samples analyzed are not 100 percent comparable—that is, whole cortex from mouse compared with a small region of human brain that may contain amyloid plaques that have a known glial scarring component associated with them. It will be interesting to determine if these signatures are common across the different pathological regions of the brain—or even which subsets of these astrocytes (or microglia) are present in early versus late stages of disease. This is not to be taken as a shortcoming of the paper at all, but just the nature of such studies that we all as a field must deal with.

    Overall this paper produces an incredibly rich data set for the field, one that will be mined heavily to determine new testable hypotheses, and particularly provide a comparative basis for any group that completes a similar single-cell analysis of other rodent AD models. The study also highlights some of the major problems we face in this field—that of cross-species differences, models that do not completely recapitulate all aspects of a disease, and differences in human postmortem sample pathologies. None of these difficulties are contained to a single laboratory, but studies like this one pave the way for expanding our combined community data set so that we can mitigate future mistakes of studying the wrong cellular responses.

    View all comments by Shane Liddelow
  2. Among the now several “-omics” papers on Alzheimer’s disease that have emerged in the last few years, this new report by Zhou et al. stands out because of its comprehensive analysis of mouse and human tissue at the single -cell level. One of the more obvious and important results of this new report is the marked difference in gene-transcript changes that are observed in human and the mouse model of disease. These findings add to a growing literature that brings into question the validity of these AD mouse models, which has worrying implications for drug discovery and disease modelling in the laboratory.

    We noted that gene-ontology analysis in microglia identified metal-ion (especially iron) homeostasis as the most significant affected pathway in microglia of AD patients. This is perhaps surprising since most iron-related genes are more prominently regulated by iron-response binding proteins at the level of translation, whereas transcripts were used in the analysis of this paper. Perhaps even more striking changes would be observed if protein were measured? Downregulation of this pathway leading to “metalostasis”—impaired trafficking of metal ions—can have substantial impact on brain health, and we believe impacts on AD pathogenesis. Indeed, our recent clinical findings (Ayton et al., 2019Ayton et al., 2017; Ayton et al., 2017; Ayton et al., 2015) and prior laboratory work (Duce et al., 2010; Lei et al., 2012) support a substantial role for the damaging effects of impaired iron trafficking in AD. The fact that oxidative pathways also emerged as significant in oligodendrocytes also suggests an important role for damaging iron chemistry in AD. Ferroptosis, a recently described cell-death pathway that is dependent on iron-induced lipid peroxidation, is a potential mechanism of neurodegeneration in AD. SEPP1, a selenium transporting protein that is required for the functioning of the master regulator of ferroptosis, GPX4, also changed significantly, and further supports this pathway in the neurodegenerative mechanism of AD.


    . Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Mol Psychiatry. 2019 Feb 18; PubMed.

    . Association of Cerebrospinal Fluid Ferritin Level With Preclinical Cognitive Decline in APOE-ε4 Carriers. JAMA Neurol. 2017 Jan 1;74(1):122-125. PubMed.

    . Cerebral quantitative susceptibility mapping predicts amyloid-β-related cognitive decline. Brain. 2017 Aug 1;140(8):2112-2119. PubMed.

    . Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. Nat Commun. 2015 May 19;6:6760. PubMed.

    . Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell. 2010 Sep 17;142(6):857-67. PubMed.

    . Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012 Feb;18(2):291-5. PubMed.

    View all comments by Ashley Bush
  3. I wish to congratulate Zhou et al. for this exceptional article. One of the genes that attracted my attention was SERPINA3 (aka alpha-1-antichymotrypsin). We published that alpha-1-antichymotrypsin (ACT) was intimately associated with amyloid plaques in AD brains (Abraham et al., 1988), and that bigenic mice overexpressing APP and ACT develop twice as many plaques as APP tg mice (Mucke et al., 2000).

    We also reported that ACT is primarily produced in reactive astrocytes (Pasternack et al., 1989; Koo et al., 1991). Finally, we showed that ACT and Aβ form a stable complex in vitro (Potter et al., 1991). We hypothesized at that time that ACT is involved in the stability of the Aβ plaques.


    . Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer's disease. Cell. 1988 Feb 26;52(4):487-501. PubMed.

    . Astroglial expression of human alpha(1)-antichymotrypsin enhances alzheimer-like pathology in amyloid protein precursor transgenic mice. Am J Pathol. 2000 Dec;157(6):2003-10. PubMed.

    . Astrocytes in Alzheimer's disease gray matter express alpha 1-antichymotrypsin mRNA. Am J Pathol. 1989 Nov;135(5):827-34. PubMed.

    . The Alzheimer amyloid components α1 antichymotrypsin and β-protein form a stable complex in vitro. Alzheimer's Disease: Basic Mechanisms, Diagnosis and Therapeutic Strategies: edited by K. Iqbal, D.R.C. McLachlan, B. Winblad and H. M. Wisniewski. 1991

    . Developmental expression of alpha 1-antichymotrypsin in brain may be related to astrogliosis. Neurobiol Aging. 1991 Sep-Oct;12(5):495-501. PubMed.

    View all comments by Carmela Abraham
  4. This is a very informative and important paper. We should remember that there are no "mouse models of AD." Maybe we will never see any animal model that fully mimics Alzheimer’s disease (see Walker and Jucker, 2017).

    What we have are mouse models that allow us to dissect many of the molecular and cellular mechanisms that drive Aβ-amyloidosis and tauopathy. As the authors point out, the microglial transcriptome in AD and murine models of Aβ-amyloidosis only partially overlap, and this finding will hopefully help to dissect the contribution of Aβ-amyloidosis to AD.


    . The Exceptional Vulnerability of Humans to Alzheimer's Disease. Trends Mol Med. 2017 Jun;23(6):534-545. Epub 2017 May 5 PubMed.

    View all comments by Mathias Jucker
  5. This is an excellent study providing new insights and a rich resource on TREM2-dependent glial responses in AD in mice and humans. One highlight of the study is the description of reactive oligodendrocytes in the 5xFAD mouse model of AD. Using snRNAseq, the authors discovered a Serpina3n+ population of oligodendrocytes reactive to Aβ plaques. These cells were also positive for carbonic anhydrase 2, providing evidence these cells are mature oligodendrocytes.

    While there is extensive literature on reactive microglia and astrocytes, we know very little about reactive oligodendrocytes. How are they formed? What are their functions? Zhou et al. show that Serpina3n+ oligodendrocytes are partially dependent on TREM2, suggesting that microglia activation is necessary to trigger reactive oligodendrocytes. Furthermore, they found that Serpina3n+ oligodendrocytes express C4b, a factor that promoted aggregation of Aβ, suggesting that the formation of reactive oligodendrocytes is a maladaptive response in the context of AD.

    When the authors compared glial responses in mouse and human, they observed important differences. Also, in human AD, oligodendrocytes appeared to be reactive, but these cells upregulated a distinct set of genes. These were genes involved in the control of osmotic, oxidative, and lipid metabolic pathways. It is, thus, conceivable that reactive oligodendrocytes also have beneficial functions, for example, by responding to neuronal injury by upregulating pathways that promote trophic and neuroprotective pathways.

    Are reactive oligodendroglia also present in other diseases? We know very little about reactive oligodendrocytes, but activated oligodendrocyte precursor cells have been described. For example, recently, the lab of Goncalo Castelo-Branco and the lab of Peter Calabresi defined activated oligodendrocyte precursor cells in models of multiple sclerosis. These cells express MHC-II and are able to activate memory and effector CD4-positive T cells. It will now be interesting to dig deeper into these largely unknown functions of reactive oligodendroglia and into the signaling pathways that lead to their activation.

    View all comments by Mikael Simons

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