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Basic Science and Pathogenesis.

Laurent Potvin-Trottier1, Robin Guay-Lord1, Lionel Breuillaud1

  • 1Biospective Inc, Montreal, QC, Canada.

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Summary
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Reactive astrocytes and microglia dynamics in Alzheimer's disease (AD) models reveal distinct spatial patterns around amyloid plaques. Morphological assessment offers sensitive measures for evaluating potential AD therapeutics.

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Area of Science:

  • Neuroscience
  • Immunology
  • Computational Biology

Background:

  • Astrocytes and microglia are key players in neurodegenerative diseases like Alzheimer's disease (AD).
  • Understanding their subtypes, roles, and interactions is crucial for elucidating disease mechanisms and identifying therapeutic targets.
  • This study investigates the spatiotemporal dynamics of astrogliosis and microgliosis within the amyloid-beta (Aβ) plaque microenvironment in an APP/PS1 transgenic mouse model of AD.

Purpose of the Study:

  • To evaluate the spatiotemporal dynamics of astrogliosis and microgliosis in the Aβ plaque microenvironment.
  • To characterize the morphology of reactive astrocytes and microglia using advanced computational methods.
  • To differentiate between vascular and non-vascular plaques and their impact on neuroinflammation.

Main Methods:

  • Developed an automated deep learning-based approach to identify, count, and localize astrocytes.
  • Utilized an explainable machine-learning (ML) model to assess astrocyte morphology and identify reactivity (hypertrophy).
  • Implemented ML models to distinguish vascular from non-vascular plaques and analyzed cellular changes in mice at 6, 9, and 12 months of age.

Main Results:

  • A novel astrocyte hypertrophy score, based on morphological features, proved more sensitive to disease progression than GFAP stain density.
  • Microglia progressively accumulate around plaques, while hypertrophic astrocytes are found more distantly and excluded from larger plaques.
  • Vascular plaques exhibited significantly less neuroinflammation compared to non-vascular plaques.

Conclusions:

  • Morphological characteristics of astrocytes provide valuable insights into their phenotype and reactivity.
  • These morphological features can serve as sensitive preclinical measures for assessing disease-modifying therapeutic agents in neurodegenerative disease models.
  • The distinct spatial-temporal dynamics of astrocytes and microglia highlight their complex roles in AD pathogenesis.