Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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}

Signature Amyloid {beta} Profiles Are Produced by Different {gamma}-Secretase Complexes.
H. Acx, L. Chavez-Gutierrez, L. Serneels, S. Lismont, M. Benurwar, N. Elad, and B. De Strooper (2014)
J. Biol. Chem. 289, 4346-4355
   Abstract »    Full Text »    PDF »
Differential, dominant activation and inhibition of Notch signalling and APP cleavage by truncations of PSEN1 in human disease.
M. Newman, L. Wilson, G. Verdile, A. Lim, I. Khan, S. H. Moussavi Nik, S. Pursglove, G. Chapman, R. N. Martins, and M. Lardelli (2014)
Hum. Mol. Genet. 23, 602-617
   Abstract »    Full Text »    PDF »
Nonmelanoma skin cancer is associated with reduced Alzheimer disease risk.
R. S. White, R. B. Lipton, C. B. Hall, and J. R. Steinerman (2013)
Neurology 80, 1966-1972
   Abstract »    Full Text »    PDF »
Alzheimer's Disease: Presenilin 2-Sparing {gamma}-Secretase Inhibition Is a Tolerable A{beta} Peptide-Lowering Strategy.
T. Borgegard, S. Gustavsson, C. Nilsson, S. Parpal, R. Klintenberg, A.-L. Berg, S. Rosqvist, L. Serneels, S. Svensson, F. Olsson, et al. (2012)
J. Neurosci. 32, 17297-17305
   Abstract »    Full Text »    PDF »
Treatment Strategies Targeting Amyloid {beta}-Protein.
D. Schenk, G. S. Basi, and M. N. Pangalos (2012)
Cold Spring Harb Perspect Med 2, a006387
   Abstract »    Full Text »    PDF »
Contribution of the {gamma}-Secretase Subunits to the Formation of Catalytic Pore of Presenilin 1 Protein.
K. Takeo, N. Watanabe, T. Tomita, and T. Iwatsubo (2012)
J. Biol. Chem. 287, 25834-25843
   Abstract »    Full Text »    PDF »
Modification of {gamma}-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease.
F. X. Guix, T. Wahle, K. Vennekens, A. Snellinx, L. Chavez-Gutierrez, G. Ill-Raga, E. Ramos-Fernandez, C. Guardia-Laguarta, A. Lleo, M. Arimon, et al. (2012)
EMBO Mol Med. 4, 660-673
   Abstract »    Full Text »    PDF »
Altered {gamma}-secretase activity in mild cognitive impairment and Alzheimer's disease.
N. Kakuda, M. Shoji, H. Arai, K. Furukawa, T. Ikeuchi, K. Akazawa, M. Takami, H. Hatsuta, S. Murayama, Y. Hashimoto, et al. (2012)
EMBO Mol Med. 4, 344-352
   Abstract »    Full Text »    PDF »
Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease.
V. Schmidt, K. Baum, A. Lao, K. Rateitschak, Y. Schmitz, A. Teichmann, B. Wiesner, C. M. Petersen, A. Nykjaer, J. Wolf, et al. (2012)
EMBO J. 31, 187-200
   Abstract »    Full Text »    PDF »
Presenilins and {gamma}-Secretase: Structure, Function, and Role in Alzheimer Disease.
B. De Strooper, T. Iwatsubo, and M. S. Wolfe (2012)
Cold Spring Harb Perspect Med 2, a006304
   Abstract »    Full Text »    PDF »
Alzheimer's Disease: The Challenge of the Second Century.
D. M. Holtzman, J. C. Morris, and A. M. Goate (2011)
Science Translational Medicine 3, 77sr1
   Full Text »    PDF »
Presenilins Promote the Cellular Uptake of Copper and Zinc and Maintain Copper Chaperone of SOD1-dependent Copper/Zinc Superoxide Dismutase Activity.
M. A. Greenough, I. Volitakis, Q.-X. Li, K. Laughton, G. Evin, M. Ho, A. H. Dalziel, J. Camakaris, and A. I. Bush (2011)
J. Biol. Chem. 286, 9776-9786
   Abstract »    Full Text »    PDF »
Prion protein and A{beta}-related synaptic toxicity impairment.
A. M. Calella, M. Farinelli, M. Nuvolone, O. Mirante, R. Moos, J. Falsig, I. M. Mansuy, and A. Aguzzi (2010)
EMBO Mol Med. 2, 306-314
   Abstract »    Full Text »    PDF »
In Vivo Reconstitution of {gamma}-Secretase in Drosophila Results in Substrate Specificity.
D. Stempfle, R. Kanwar, A. Loewer, M. E. Fortini, and G. Merdes (2010)
Mol. Cell. Biol. 30, 3165-3175
   Abstract »    Full Text »    PDF »
Role of Presenilins in Neuronal Calcium Homeostasis.
H. Zhang, S. Sun, A. Herreman, B. De Strooper, and I. Bezprozvanny (2010)
J. Neurosci. 30, 8566-8580
   Abstract »    Full Text »    PDF »
Aph-1 Associates Directly with Full-length and C-terminal Fragments of {gamma}-Secretase Substrates.
A. C. Chen, L. Y. Guo, B. L. Ostaszewski, D. J. Selkoe, and M. J. LaVoie (2010)
J. Biol. Chem. 285, 11378-11391
   Abstract »    Full Text »    PDF »
Proteases and Proteolysis in Alzheimer Disease: A Multifactorial View on the Disease Process.
B. De Strooper (2010)
Physiol Rev 90, 465-494
   Abstract »    Full Text »    PDF »
Pharmacological Analysis of Drosophila melanogaster {gamma}-Secretase with Respect to Differential Proteolysis of Notch and APP.
C. Groth, W. G. Alvord, O. A. Quinones, and M. E. Fortini (2010)
Mol. Pharmacol. 77, 567-574
   Abstract »    Full Text »    PDF »
{gamma}-Secretase Composed of PS1/Pen2/Aph1a Can Cleave Notch and Amyloid Precursor Protein in the Absence of Nicastrin.
G. Zhao, Z. Liu, Ma. X. G. Ilagan, and R. Kopan (2010)
J. Neurosci. 30, 1648-1656
   Abstract »    Full Text »    PDF »
Modeling an Anti-Amyloid Combination Therapy for Alzheimer's Disease.
V. W. Chow, A. V. Savonenko, T. Melnikova, H. Kim, D. L. Price, T. Li, and P. C. Wong (2010)
Science Translational Medicine 2, 13ra1
   Abstract »    Full Text »    PDF »
Epigenetic control of aquaporin 1 expression by the amyloid precursor protein.
S. Huysseune, P. Kienlen-Campard, S. Hebert, B. Tasiaux, K. Leroy, O. Devuyst, J.-P. Brion, B. De Strooper, and J.-N. Octave (2009)
FASEB J 23, 4158-4167
   Abstract »    Full Text »    PDF »
Avoiding Unintended Toxicity.
T. E. Golde and T. L. Kukar (2009)
Science 324, 603-604
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882