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Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase
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Erlin-2 is associated with active γ-secretase in brain and affects amyloid β-peptide production

Yasuhiro Teranishi1, Ji-Yeun Hur, Gucci Jijuan Gu

  • 1Karolinska Institutet Dainippon Sumitomo Pharma Alzheimer Center, KI-Alzheimer Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum, Stockholm SE-141 86, Sweden.

Biochemical and Biophysical Research Communications
|July 10, 2012
PubMed

Insights

Researchers discovered erlin-2, a novel protein associated with gamma-secretase, which influences amyloid beta-peptide (Aβ) production. This finding is crucial for developing targeted Alzheimer disease therapies by selectively inhibiting Aβ generation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • The gamma-secretase complex cleaves amyloid precursor protein (APP) to produce neurotoxic amyloid beta-peptide (Aβ), a key factor in Alzheimer disease pathogenesis.
  • Selective inhibition of APP processing by gamma-secretase is a therapeutic challenge due to its numerous other substrates.
  • Gamma-secretase associated proteins (GSAPs) are implicated in substrate selection and processing.

Purpose of the Study:

  • To identify novel GSAPs involved in gamma-secretase substrate processing.
  • To investigate the role of identified GSAPs in Aβ production and Alzheimer disease.
  • To explore potential therapeutic strategies targeting specific gamma-secretase interactions.

Main Methods:

  • Affinity purification of gamma-secretase and associated proteins using a specific inhibitor.
  • Tandem mass spectrometry for protein identification.
  • Co-immunoprecipitation and proximity ligation assays to confirm protein interactions.
  • siRNA experiments to assess the functional impact of erlin-2 on Aβ and Notch processing.

Main Results:

  • A novel brain GSAP, erlin-2, was identified and found to associate with gamma-secretase.
  • Erlin-2 predominantly resides in detergent-resistant membranes (DRMs) and its association with gamma-secretase is higher in DRMs.
  • Reduced erlin-2 levels led to decreased Aβ production with minimal impact on Notch processing.

Conclusions:

  • Erlin-2 is a novel brain-specific GSAP that interacts with gamma-secretase within DRMs.
  • Erlin-2 plays a role in modulating Aβ production, suggesting it as a potential therapeutic target for Alzheimer disease.
  • The findings highlight the importance of GSAPs in understanding and targeting gamma-secretase activity.

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