2. Academic Validation
  3. The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4

The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4

  • bioRxiv. 2024 Jul 3:2024.07.01.601474. doi: 10.1101/2024.07.01.601474.
Femke M Feringa 1,  Sascha J Koppes-den Hertog 1 2,  Lian Wang 3,  Rico J E Derks 3,  Iris Kruijff 1 2,  Lena Erlebach 4 5,  Jorin Heijneman 1 2,  Ricardo Miramontes 6 7 8,  Nadine Pömpner 9,  Niek Blomberg 3,  Damien Olivier-Jimenez 3,  Lill Eva Johansen 1,  Alexander J Cammack 10 11,  Ashling Giblin 10 11,  Christina E Toomey 12,  Indigo V L Rose 13,  Hebao Yuan 14,  Michael Ward 14,  Adrian M Isaacs 10 11,  Martin Kampmann 15,  Deborah Kronenberg-Versteeg 4 5,  Tammaryn Lashley 10,  Leslie M Thompson 6 7 8,  Alessandro Ori 9,  Yassene Mohammed 3 16,  Martin Giera 3,  Rik van der Kant 1 2
Affiliations

Affiliations

  • 1 Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands.
  • 2 Alzheimer Center Amsterdam, Department of Neurology, Amsterdam University Medical Center, Amsterdam Neuroscience, Amsterdam, the Netherlands.
  • 3 Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, the Netherlands.
  • 4 German Center for Neurodegenerative Diseases (DZNE) Tübingen, Tübingen, Germany.
  • 5 Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 6 Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
  • 7 Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.
  • 8 Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.
  • 9 Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.
  • 10 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
  • 11 UK Dementia Research Institute at UCL, University College London, London, UK.
  • 12 Department of Clinical and Molecular Neuroscience, Queen Square Institute of Neurology, University College London, London, UK.
  • 13 Institute for Neurodegenerative Diseases and Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • 14 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 15 Department of Biochemistry and Biophysics, Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA.
  • 16 Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada.
PMID: 39005258 DOI: 10.1101/2024.07.01.601474
Abstract

Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulate in vivo lipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives Cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that Cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I antigen presentation. We show that through enhanced Cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.

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