Thomas Franz Erich Willnow

Apolipoprotein E4 disrupts the neuroprotective action of sortilin in neuronal lipid metabolism and endocannabinoid signaling

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  • alz.12121

    Final published version, 5.81 MB, PDF document

DOI

  • Antonino Asaro, Max Delbrueck Center for Molecular Medicine
  • ,
  • Anne-Sophie Carlo-Spiewok, Max Delbrueck Center for Molecular Medicine
  • ,
  • Anna R Malik, Max Delbrueck Center for Molecular Medicine
  • ,
  • Michael Rothe, Medizinische Hochschule, Hanover, Germany; Private Practice Lübeck, Germany
  • ,
  • Carola G Schipke, Charité – Universitätsmedizin Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Institute of Health and Nursing Science, Berlin, Germany
  • ,
  • Oliver Peters, German Center for Neurodegenerative Diseases
  • ,
  • Joerg Heeren, University Medical Center Hamburg-Eppendorf
  • ,
  • Thomas E Willnow

INTRODUCTION: Apolipoprotein E (apoE) is a carrier for brain lipids and the most important genetic risk factor for Alzheimer's disease (AD). ApoE binds the receptor sortilin, which mediates uptake of apoE-bound cargo into neurons. The significance of this uptake route for brain lipid homeostasis and AD risk seen with apoE4, but not apoE3, remains unresolved.

METHODS: Combining neurolipidomics in patient specimens with functional studies in mouse models, we interrogated apoE isoform-specific functions for sortilin in brain lipid metabolism and AD.

RESULTS: Sortilin directs the uptake and conversion of polyunsaturated fatty acids into endocannabinoids, lipid-based neurotransmitters that act through nuclear receptors to sustain neuroprotective gene expression in the brain. This sortilin function requires apoE3, but is disrupted by binding of apoE4, compromising neuronal endocannabinoid metabolism and action.

DISCUSSION: We uncovered the significance of neuronal apoE receptor sortilin in facilitating neuroprotective actions of brain lipids, and its relevance for AD risk seen with apoE4.

Original languageEnglish
JournalAlzheimer's & dementia : the journal of the Alzheimer's Association
Volume16
Issue9
Pages (from-to)1248-1258
Number of pages11
ISSN1552-5260
DOIs
Publication statusPublished - Sep 2020

Bibliographical note

© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

    Research areas

  • Alzheimer's disease, DHA, VPS10P domain receptors, apolipoprotein E, brain lipoprotein metabolism, endocannabinoids, lipoprotein receptors, polyunsaturated fatty acids

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