In recent years, research has implicated microglia ever more deeply in neurodegenerative diseases, yet exactly how these cells act in specific clinical dementia syndromes still needs to be refined. In the November 18 Cell Reports, researchers led by Jessica Rexach and Daniel Geschwind from the University of California, Los Angeles, examined microglial gene-expression networks from different stages of tauopathies. They found microglial transcriptome modules that emerge at different phases of disease. Their findings suggest that microglia responses go far beyond the binary, i.e., normal and disease-associated. In fact, microglia respond dynamically, with different subpopulations emerging over the course of a disease. Their states range from responding to early peptide irritants, to a subsequent anti-viral defensive crouch. Ultimately, microglia morph from what the authors call a neuroimmune activation state (NAct) to an immunosuppressed state (NSupp).
- In tauopathy models, microglia responses are not binary, but dynamic.
- Distinct microglial states emerge at different stages.
- The immune suppression module USP18 modulates pro-inflammatory pathways.
- Neurodegeneration features competing arms of microglial-immune activation (NAct) and suppression (NSupp).
“The authors performed an extensive and comprehensive bioinformatic analysis on microglia in tau-associated neurodegeneration models,” said Marco Colonna from Washington University, St. Louis. “The fact that signatures of both neuroimmune activation and neuroimmune suppression coexist in microglia in response to neurodegeneration is intriguing, as it suggests bi-functional roles of microglia—the balance of which may modulate disease progression.”
Rexach and colleagues analyzed bulk tissue transcriptomes and purified microglia from mouse and human control, Alzheimer’s disease, frontotemporal dementia-Pick’s disease, and progressive supranuclear palsy. This uncovered expression modules that emerged at different phases of the disease and gave the microglia successive functional “identities”—some early in disease, some in the middle, and some at late stages. The changes in gene-expression networks seen in these modules correlated with the phosphorylation of tau at serine 231, a marker of impending tau pathology.
The authors discovered that the earliest microglial identity is proliferating and features receptors that respond to peptides in the environment, for example tau. Expression of these receptors persists, but later expression modules add on sensors for lipids, which are thought to activate immune responses. At this stage, the microglia are phagocytic. Nucleotide damage signals then activate double-stranded RNA receptors, which are required for microglia to respond to viral invaders, or to damaged DNA and chromatin. The final microglial identity is characterized by chronic viral response pathways, along with pathways that were previously downregulated at earlier stages, such as the type 2 interferon response. This time course suggests that tau aggregates damage microglial DNA and lead to abnormal double-stranded RNA, which looks to the cell like a viral infection. This then turns on the microglial type 1 interferon anti-viral response, and ultimately, the microglia enter a period of partial immune suppression and a subsequent increase in type 2 interferon signaling. At this point, microglial cell death by apoptosis is rampant (see image below).
“There is a co-expression of these receptors; as the disease progresses, the microglia add new receptors,” Rexach told Alzforum.
Getting Worse. Microglia gene expression transitions from a response to abnormal peptides, to adding lipid and nucleotide sensors, which enable microglia to respond to viral invaders or damaged DNA and chromatin. Type 1 interferon anti-viral response is then activated, ultimately leading to partial immune suppression, type 2 interferon response, and neurodegeneration.
The authors correlated these microglial neurodegeneration modules with known risk genes for AD, frontotemporal dementia, and progressive supranuclear palsy as found in GWAS, in order to see how genetic risk and microglial expression relate to each other. They report that FTD and PSP genetic risk factors show up disproportionately in the early persistent peptide response, whereas AD risks tend to cluster in the later-stage viral defense response. Since tau mutations cause FTD and PSP, but not AD, the finding suggests that the microglial response in AD is different than in the other two tauopathies. In other words, genetic causes of AD versus FTD and PSP influence distinct aspects of microglial biology in these diseases.
Rexach and colleagues also found sub-modules they dubbed neuroimmune activation and neuroimmune suppression. Both crop up early in the disease. NAct genes are turned on first, i.e., in response to pathological tau. Activated slightly later by type 1 interferon, NSupp then suppresses NAct. The authors identified the gene Usp18 as a hub in the immune suppression module. USP18 modulates NSupp response and partially inhibits upregulation of microglial NAct in mouse and human AD, FTP, and PSP disease models (see image below).
Microglial immune suppression. Nucleotide detection from damaged cells activates type 1 interferon to suppress microglia activity in disease.
The authors proposed a model whereby early in tauopathies, some extracellular stimuli, such as Aβ for AD or tau for FTD or PSP, activates the NAct pathway. As disease progresses, separate stimuli turn on NSupp genes, which in turn shut down NAct. This model suggests that early peptide stimuli trigger a beneficial response that eventually gets overridden. The authors tested this empirically in cultured microglia, showing that type 1 interferon suppressed pro-inflammatory cytokines released in response to the early stimuli. The NAct and NSupp module genes were also more highly expressed in postmortem tissue from FTD and PSP patients compared to age-matched controls.
Overall, these findings organize tauopathy disease-expression pathways into distinct microglial modules that are linked to progressive stages of neurodegeneration and show up in genetically diverse mouse models and the human brain.
“We hope this study offers clear and specific data to think about the dynamic aspects of microglia responses across stages of neurodegeneration and, importantly, help scientists recognize that the different modules interact with one another,” said Rexach. “Going forward in this field, it’s key to appreciate that these cells are all communicating with each other.”—Helen Santoro
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- Rexach JE, Polioudakis D, Yin A, Swarup V, Chang TS, Nguyen T, Sarkar A, Chen L, Huang J, Lin LC, Seeley W, Trojanowski JQ, Malhotra D, Geschwind DH. Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression. Cell Rep. 2020 Nov 17;33(7):108398. PubMed.