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<p>Microglia are implicated in aging, neurodegeneration and Alzheimer’s disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to microenvironments, this spectrum enables the identification of proteomic trends across the microglia of ten cognitively normal individuals and orthogonally with single-nuclei epigenetic analysis, revealing associated molecular functions. Notably, AD tissues exhibit regulatory shifts in the immunologically active cells at the end of the proteomic spectrum, including enrichment of CD33 and CD44 and decreases in HLA-DR, P2RY12 and ApoE expression. These findings establish an in situ, single-cell spatial proteomic framework for AD-specific microglial states.</p>

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Spatial proteomics of Alzheimer’s disease-specific human microglial states

  • 期刊论文

  • 发表日期：

    2025年7月22日

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  • Dunja Mrdjen,
  • Bryan J. Cannon,
  • Meelad Amouzgar,
  • YeEun Kim,
  • Candace Liu,
  • Kausalia Vijayaragavan,
  • Christine Camacho,
  • Angie Spence,
  • Erin F. McCaffrey,
  • Anusha Bharadwaj,
  • Dmitry Tebaykin,
  • Syed Bukhari,
  • Marc Bosse,
  • Felix J. Hartmann,
  • Adam Kagel,
  • John Paul Oliveria,
  • Koya Yakabi,
  • Geidy E. Serrano,
  • Maria M. Corrada,
  • Claudia H. Kawas,
  • Robert Tibshirani,
  • Thomas G. Beach,
  • M. Ryan Corces,
  • Will Greenleaf,
  • R. Michael Angelo,
  • Thomas Montine,
  • Sean C. Bendall

摘要

Microglia are implicated in aging, neurodegeneration and Alzheimer’s disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to microenvironments, this spectrum enables the identification of proteomic trends across the microglia of ten cognitively normal individuals and orthogonally with single-nuclei epigenetic analysis, revealing associated molecular functions. Notably, AD tissues exhibit regulatory shifts in the immunologically active cells at the end of the proteomic spectrum, including enrichment of CD33 and CD44 and decreases in HLA-DR, P2RY12 and ApoE expression. These findings establish an in situ, single-cell spatial proteomic framework for AD-specific microglial states.