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Microglia show distinct changes in progressive supranuclear palsy (PSP), with increased numbers and altered morphology, particularly in white matter. Single-cell analysis reveals unique PSP-specific microglial subtypes.

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Area of Science:

  • Neuroscience
  • Immunology
  • Pathology

Background:

  • Microglia are crucial in neurodegenerative diseases, but their specific roles and diversity in conditions like progressive supranuclear palsy (PSP) are not well understood.
  • PSP is a tauopathy with significant neuronal and glial tau pathology, yet microglial involvement remains under-investigated.
  • Microglial diversity, characterized by varied morphology and function, is increasingly recognized, especially with single-cell technologies.

Purpose of the Study:

  • To investigate the morphological and functional characteristics of microglia in the frontal cortex of individuals with PSP.
  • To identify PSP-specific microglial subtypes and their gene expression profiles.
  • To compare PSP-associated microglial changes with known microglial subtypes.

Main Methods:

  • Immunohistochemistry for microglial markers (Iba1, HLA-DR) in PSP and control frontal cortex samples.
  • Quantitative analysis of microglial load and morphology using HALO® software.
  • Single-cell RNA sequencing (snRNA-seq) to identify differentially expressed genes and microglial subclusters in PSP.

Main Results:

  • Increased Iba1-positive microglia in white matter and HLA-DR-positive microglia in both cortex and white matter of PSP cases.
  • PSP microglia exhibited altered morphology, including longer processes, increased branching, and larger cell bodies, especially in white matter.
  • snRNA-seq identified four PSP-specific microglial subclusters with distinct gene expression patterns, including homeostatic, MHC class II, and aging-related genes.

Conclusions:

  • This study highlights unique microglial morphological and functional signatures in the PSP-affected frontal cortex.
  • The findings suggest distinct microglial responses in PSP, differing from previously characterized subtypes.
  • Further research into these specific microglial characteristics could offer new therapeutic targets for PSP.