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-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease
Lutgarde Serneels,1,2,*Jérôme Van Biervliet,1,2,*Katleen Craessaerts,1,2Tim Dejaegere,1,2Katrien Horré,1,2Tine Van Houtvin,1,2Hermann Esselmann,3,4Sabine Paul,3,4Martin K. Schäfer,5Oksana Berezovska,6Bradley T. Hyman,6Ben Sprangers,7Raf Sciot,8Lieve Moons,9Mathias Jucker,10Zhixiang Yang,11Patrick C. May,11Eric Karran,12,Jens Wiltfang,3,4Rudi D’Hooge,13Bart De Strooper1,2,
The -secretase complex plays a role in Alzheimer’s disease and cancer progression. The development of clinically usefulinhibitors, however, is complicated by the role of the -secretasecomplex in regulated intramembrane proteolysis of Notch andother essential proteins. Different -secretase complexes containingdifferent Presenilin or Aph1 protein subunits are present invarious tissues. Here we show that these complexes have heterogeneousbiochemical and physiological properties. Specific inactivationof the Aph1B -secretase in a mouse Alzheimer’s diseasemodel led to improvements of Alzheimer’s disease–relevantphenotypic features without any Notch-related side effects.The Aph1B complex contributes to total -secretase activity inthe human brain, and thus specific targeting of Aph1B-containing-secretase complexes may help generate less toxic therapiesfor 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.
Present address: Johnson and Johnson, Pharmaceutical Researchand Development, 2340 Beerse, Belgium.
To whom correspondence should be addressed. E-mail: bart.destrooper{at}med.kuleuven.be
-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease
-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 
Present address: Johnson and Johnson, Pharmaceutical Research and Development, 2340 Beerse, Belgium. 
To whom correspondence should be addressed. E-mail: 
