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Science 324 (5927): 639-642

Copyright © 2009 by the American Association for the Advancement of Science

{gamma}-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease

Lutgarde Serneels,1,2,* Jérôme Van Biervliet,1,2,* Katleen Craessaerts,1,2 Tim Dejaegere,1,2 Katrien Horré,1,2 Tine Van Houtvin,1,2 Hermann Esselmann,3,4 Sabine Paul,3,4 Martin K. Schäfer,5 Oksana Berezovska,6 Bradley T. Hyman,6 Ben Sprangers,7 Raf Sciot,8 Lieve Moons,9 Mathias Jucker,10 Zhixiang Yang,11 Patrick C. May,11 Eric Karran,12,{dagger} Jens Wiltfang,3,4 Rudi D’Hooge,13 Bart De Strooper1,2,{ddagger}

Abstract: The {gamma}-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 {gamma}-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different {gamma}-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 {gamma}-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 {gamma}-secretase activity in the human brain, and thus specific targeting of Aph1B-containing {gamma}-secretase complexes may help generate less toxic therapies for Alzheimer’s disease.

1 Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
2 Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
3 Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
4 Department of Psychiatry and Psychotherapy, Rhine State Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany.
5 Department of Molecular Neurosciences, Institute of Anatomy and Cell Biology, Philipps University, D-35032 Marburg, Germany.
6 Harvard Medical School, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disorders, Charlestown, MA 02129, USA.
7 Laboratory of Experimental Transplantation, KULeuven, 3000 Leuven, Belgium.
8 Laboratory of Morphology and Molecular Pathology, KULeuven, 3000 Leuven, Belgium.
9 Laboratory of Neural Circuit Development and Regeneration, Department of Biology, KULeuven, 3000 Leuven, Belgium.
10 Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.
11 Neuroscience Discovery Research, Lilly Research Labs, Eli Lilly and Co., Indianapolis, IN 46285, USA.
12 Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.
13 Laboratory of Biological Psychology, Department of Psychology, KULeuven, 3000 Leuven, Belgium.

* These authors contributed equally to this work.

{dagger} Present address: Johnson and Johnson, Pharmaceutical Research and Development, 2340 Beerse, Belgium.

{ddagger} To whom correspondence should be addressed. E-mail: bart.destrooper{at}med.kuleuven.be

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