Distinct amyloid-beta and tau-associated microglia profiles in Alzheimer's disease

Emma Gerrits, Nieske Brouwer, Susanne M. Kooistra, Maya E. Woodbury, Yannick Vermeiren, Mirjam Lambourne, Jan Mulder, Markus Kummer, Thomas Moller, Knut Biber, Wilfred F. A. den Dunnen, Peter P. De Deyn, Bart J. L. Eggen, Erik W. G. M. Boddeke*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-beta and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-beta and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-beta plaques or both amyloid-beta plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-beta load and localized to amyloid-beta plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.

Original languageEnglish
Number of pages16
JournalActa Neuropathologica
DOIs
Publication statusPublished - 20-Feb-2021

Keywords

  • Microglia
  • Alzheimer&#8217
  • s disease
  • Single-nucleus RNA sequencing
  • Amyloid-&#946
  • Tau

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