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Membrane lipid remodeling modulates γ-secretase processivity.

Edgar Dawkins1, Rico J E Derks2, Martina Schifferer3

  • 1Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center (BMC), LMU Munich, Munich, Germany.

The Journal of Biological Chemistry
|February 22, 2023
PubMed
Summary
This summary is machine-generated.

Erucic acid (EA) alters cell membrane lipids, impacting amyloid-β (Aβ) production in Alzheimer

Keywords:
Alzheimer diseaseAβ37/38amyloid precursor protein (APP) processingamyloid-β peptide (Aβ)erucic acidlipid homeostasislipidomicsmembrane thicknesspresenilinγ-secretase

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Amyloid-β (Aβ) peptide imbalances from β- and γ-secretase dysregulation are implicated in Alzheimer's disease (AD).
  • Previous cell-free studies suggested membrane thickness influences Aβ generation by γ-secretase, but in-cell relevance was unclear.

Purpose of the Study:

  • To investigate if erucic acid (EA)-induced membrane lipid remodeling affects Aβ production in cellular models of AD.
  • To determine the impact of EA on γ-secretase activity and Aβ species generation within cells.

Main Methods:

  • Utilized AD cell models treated with erucic acid (EA).
  • Analyzed lipidome alterations and EA esterification in cell membranes.
  • Assessed γ-secretase processivity and Aβ peptide production (e.g., Aβ37, Aβ38).
  • Compared Aβ secretion in cells with wild-type (WT) versus familial AD mutant γ-secretase.

Main Results:

  • EA induced significant lipidome alterations and EA esterification in membrane lipids.
  • Membrane remodeling enhanced γ-secretase processivity, increasing beneficial Aβ37/Aβ38 production.
  • EA stimulated total Aβ secretion in WT γ-secretase cells but reduced it in familial AD mutant γ-secretase cells.

Conclusions:

  • EA-mediated membrane composition changes trigger complex lipid homeostatic responses.
  • These lipid changes differentially impact amyloidogenic processing and γ-secretase activity.
  • Findings offer critical insights for developing lipid-based therapeutic strategies for Alzheimer's disease.