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Published on: June 14, 2020
Basic Science and Pathogenesis
Johannes C M Schlachetzki1, Yi Zhou2, Nathan Spann2
1University of California, San Diego, San Diego, CA, USA.
Background:
Beyond the progressive accumulation of amyloid-beta and hyperphosphorylated tau, Alzheimer's disease (AD) is accompanied by phenotypic changes in microglia, the innate immune cells of the brain. In particular, microglia in the vicinity of Amyloid-plaques, also known as MGnD or DAM, are defined by distinct changes in their gene expression signature, e.g., upregulation of Trem2 mRNA. However, the precise transcriptional mechanism that drives microglia phenotype in response to amyloid is not defined.
Method:
Here, we isolated microglia from the APP/PS1 transgenic mouse model followed by ATAC-seq.
Result:
We provide evidence for a model in which differential activation of a common set of transcriptional regulators that includes members of the MITF/TFE, AP-1 and EGR transcription factor families drives the amyloid-plaque associated microglia phenotype.
Conclusion:
Collectively, these findings reveal the framework of the transcriptional circuitry that is used to establish a range of neurodegenerative pathology-associated microglia phenotypes.
Insights
Alzheimer's disease involves microglia changes near amyloid plaques. Transcription factors like MITF/TFE, AP-1, and EGR drive these specific microglia (MGnD/DAM) phenotypes in the brain.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) pathology includes amyloid-beta and tau accumulation.
- Microglia, the brain's innate immune cells, exhibit distinct phenotypic changes in AD, particularly near amyloid plaques (MGnD/DAM).
- Key genes like Trem2 mRNA are upregulated in plaque-associated microglia, but the underlying transcriptional mechanisms remain unclear.
Purpose of the Study:
- To elucidate the transcriptional mechanisms driving the specific phenotype of microglia in response to amyloid pathology.
- To identify the key transcription factor families involved in regulating microglia activation in Alzheimer's disease.
Main Methods:
- Isolation of microglia from the APP/PS1 transgenic mouse model of Alzheimer's disease.
- Application of Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to analyze chromatin accessibility.
Main Results:
- Differential activation of specific transcriptional regulators, including MITF/TFE, AP-1, and EGR families, was identified.
- These transcription factors are shown to drive the amyloid-plaque-associated microglia phenotype.
Conclusions:
- A model is proposed where common transcriptional regulators orchestrate microglia responses to amyloid.
- These findings reveal the transcriptional circuitry underlying neurodegenerative pathology-associated microglia phenotypes.
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