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Basic Science and Pathogenesis.

Johannes C M Schlachetzki1, Yi Zhou2, Nathan Spann2

  • 1University of California, San Diego, San Diego, CA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
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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.

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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.