CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

Chritica Lodder, Isabelle Scheyltjens, Ilie Cosmin Stancu, Pablo Botella Lucena, Manuel Gutiérrez de Ravé, Sarah Vanherle, Tim Vanmierlo, Niels Cremers, Hannah Vanrusselt, Bert Brône, Bernard Hanseeuw, Jean-Noël Octave, Astrid Bottelbergs, Kiavash Movahedi, Ilse Dewachter

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of AD. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.

Original languageEnglish
Article number108
Number of pages21
JournalActa Neuropathologica Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 8 Jun 2021

Keywords

  • ATN-continuum
  • Alzheimer’s disease
  • Amyloid pathology
  • CSF1R inhibition
  • Microglial profiling
  • Neurodegeneration
  • Tau pathology

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