Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease

Thursday June 25, 2020  9:00 AM PDT / 12pm EDT

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Glia have been implicated in Alzheimer’s disease (AD)pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified apreviously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microgliain peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

In this webinar, you'll learn:

  • About the effects of the Trem2 AD risk variant on distinct cell types.
  • How single cell sequencing can reveal novel functional phenotypes of neural cells in disease
  • Previously undescribed roles of glia in AD pathogenesis.
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Yingyue Zhou
Laboratory of Marco Colonna, MD
Washington University, St. Louis
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Jeremy Petravicz, PhD
Wiley/Current Protocols Moderator
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