γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease

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Science  01 May 2009:
Vol. 324, Issue 5927, pp. 639-642
DOI: 10.1126/science.1171176

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The γ-secretase complex plays a role in Alzheimer’s disease and cancer progression. The development of clinically useful inhibitors, however, is complicated by the role of the γ-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different γ-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B γ-secretase in a mouse Alzheimer’s disease model led to improvements of Alzheimer’s disease–relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total γ-secretase activity in the human brain, and thus specific targeting of Aph1B-containing γ-secretase complexes may help generate less toxic therapies for Alzheimer’s disease.

  • * These authors contributed equally to this work.

  • Present address: Johnson and Johnson, Pharmaceutical Research and Development, 2340 Beerse, Belgium.

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