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gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease

Lutgarde Serneels1, Jérôme Van Biervliet, Katleen Craessaerts

  • 1Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium.

Science (New York, N.Y.)
|March 21, 2009
PubMed

Insights

Targeting Aph1B gamma-secretase complexes may offer a less toxic Alzheimer's disease therapy. Specific inactivation improved Alzheimer's models without Notch side effects, showing Aph1B

Area of Science:

  • Biochemistry
  • Neuroscience
  • Molecular Biology

Background:

  • The gamma-secretase complex is implicated in Alzheimer's disease and cancer.
  • Its role in cleaving essential proteins like Notch complicates therapeutic inhibitor development.
  • Heterogeneity in gamma-secretase complexes, due to varying subunits, affects function.

Purpose of the Study:

  • To investigate the distinct biochemical and physiological properties of different gamma-secretase complexes.
  • To evaluate the therapeutic potential of specifically targeting Aph1B-containing gamma-secretase complexes in an Alzheimer's disease model.

Main Methods:

  • Utilized a mouse model of Alzheimer's disease.
  • Performed specific inactivation of the Aph1B gamma-secretase subunit.
  • Assessed Alzheimer's disease-relevant phenotypic features and Notch-related side effects.

Main Results:

  • Specific inactivation of Aph1B gamma-secretase improved Alzheimer's disease-relevant phenotypes.
  • No Notch-related side effects were observed following Aph1B inactivation.
  • Aph1B-containing complexes contribute to gamma-secretase activity in the human brain.

Conclusions:

  • Aph1B gamma-secretase complexes are key contributors to Alzheimer's disease pathology.
  • Targeting Aph1B-containing gamma-secretase complexes represents a promising strategy for developing less toxic Alzheimer's therapies.
  • The heterogeneity of gamma-secretase complexes allows for targeted therapeutic interventions.

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