APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia

  • EMBO Mol Med. 2024 Dec;16(12):3113-3141. doi: 10.1038/s44321-024-00162-7.
Pranav Preman  1  2 ,  Daan Moechars  1  2 ,  Emre Fertan  3  4 ,  Leen Wolfs  1  2 ,  Lutgarde Serneels  1  2 ,  Disha Shah  1  2 ,  Jochen Lamote  5 ,  Suresh Poovathingal  1 ,  An Snellinx  1  2 ,  Renzo Mancuso  6  7 ,  Sriram Balusu  1  2 ,  David Klenerman  3  4 ,  Amaia M Arranz  8  9 ,  Mark Fiers  10  11 ,  Bart De Strooper  12  13  14
Affiliations
  • 1. VIB Center for Brain & Disease Research, Leuven, Belgium.
  • 2. Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.
  • 3. Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
  • 4. UK Dementia Research Institute, University of Cambridge, Cambridge, UK.
  • 5. VIB FACS Expertise Center, Center for Cancer Biology, Leuven, Belgium.
  • 6. Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB-UAntwerp, Centre for Molecular Neurology, Antwerp, Belgium.
  • 7. Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
  • 8. Laboratory of Humanized Models of Disease, Achucarro Basque Center for Neuroscience, Leioa, Spain.
  • 9. Ikerbasque Basque Foundation for Science, Bilbao, Spain.
  • 10. VIB Center for Brain & Disease Research, Leuven, Belgium. [email protected].
  • 11. Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium. [email protected].
  • 12. VIB Center for Brain & Disease Research, Leuven, Belgium. [email protected].
  • 13. Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium. [email protected].
  • 14. UK Dementia Research Institute, University College London, London, UK. [email protected].
PMID: 39528861 DOI: 10.1038/s44321-024-00162-7
Abstract

The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by apoE expressed in microglia or astrocytes is debated. We express here the human apoE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of apoE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in apoE mediated amyloid plaque pathology and in the induction of associated microglia responses.

Keywords
APOE; Alzheimer’s Disease; Astrocytes; Microglia; β-amyloid Pathology.
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