QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, July 18, 2007, 27(29):7817-7826; doi:10.1523/JNEUROSCI.1026-07.2007

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Ring, S. Articles by Müller, U. C. Search for Related Content PubMed PubMed Citation Articles by Ring, S. Articles by Müller, U. C.

 Previous Article  |  Next Article 

Neurobiology of Disease
The Secreted ß-Amyloid Precursor Protein Ectodomain APPs Is Sufficient to Rescue the Anatomical, Behavioral, and Electrophysiological Abnormalities of APP-Deficient Mice

Sabine Ring,^1,2 Sascha W. Weyer,¹ Susanne B. Kilian,³ Elaine Waldron,⁴ Claus U. Pietrzik,⁴ Mikhail A. Filippov,^1,2 Jochen Herms,⁵ Christian Buchholz,⁶ Christopher B. Eckman,⁷ Martin Korte,³ David P. Wolfer,⁸ and Ulrike C. Müller^1,2

¹Department of Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, D-69120 Heidelberg, Germany, ²Department of Neurochemistry, Max Planck Institute for Brain Research, D-60598 Frankfurt, Germany, ³Zoological Institute, Technical University Braunschweig, D-38106 Braunschweig, Germany, ⁴Department of Molecular Neurodegeneration, Institute of Physiological Chemistry and Pathobiochemistry, University of Mainz, D-55099 Mainz, Germany, ⁵Center for Neuropathology and Prion Research, München University, D-81377 München, Germany, ⁶Paul Ehrlich Institute, D-63225 Langen, Germany, ⁷Mayo Clinic, Jacksonville, Florida 32224, and ⁸Institute of Anatomy, University of Zürich and Department of Biology, Eidgenössische Technische Hochschule Zürich, CH-8057 Zürich, Switzerland

Correspondence should be addressed to Ulrike Müller at the above address. Email: u.mueller{at}urz.uni-hd.de

It is well established that the proteolytic processing of the ß-amyloid precursor protein (APP) generates ß-amyloid (Aß), which plays a central role in the pathogenesis of Alzheimer's disease (AD). In contrast, the physiological role of APP and of its numerous proteolytic fragments and the question of whether a loss of these functions contributes to AD are still unknown. To address this question, we replaced the endogenous APP locus by gene-targeted alleles and generated two lines of knock-in mice that exclusively express APP deletion variants corresponding either to the secreted APP ectodomain (APPs) or to a C-terminal (CT) truncation lacking the YENPTY interaction motif (APPCT15). Interestingly, the CT15 deletion resulted in reduced turnover of holoAPP, increased cell surface expression, and strongly reduced Aß levels in brain, likely because of reduced processing in the endocytic pathway. Most importantly, we demonstrate that in both APP knock-in lines the expression of APP N-terminal domains either grossly attenuated or completely rescued the prominent deficits of APP knock-out mice, such as reductions in brain and body weight, grip strength deficits, alterations in circadian locomotor activity, exploratory activity, and the impairment in spatial learning and long-term potentiation. Together, our data suggest that the APP C terminus is dispensable and that APPs is sufficient to mediate the physiological functions of APP assessed by these tests.

Key words: Alzheimer's disease; ß-amyloid precursor protein; APPs; physiological functions; knock-out; LTP

---

Received March 7, 2007; revised June 6, 2007; accepted June 7, 2007.

Correspondence should be addressed to Ulrike Müller at the above address. Email: u.mueller{at}urz.uni-hd.de

This article has been cited by other articles:

				F. Tippmann, J. Hundt, A. Schneider, K. Endres, and F. Fahrenholz Up-regulation of the {alpha}-secretase ADAM10 by retinoic acid receptors and acitretin FASEB J, June 1, 2009; 23(6): 1643 - 1654. [Abstract] [Full Text] [PDF]

				I. Y. Tamboli, K. Prager, D. R. Thal, K. M. Thelen, I. Dewachter, C. U. Pietrzik, P. St. George-Hyslop, S. S. Sisodia, B. De Strooper, M. T. Heneka, et al. Loss of {gamma}-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis J. Neurosci., November 12, 2008; 28(46): 12097 - 12106. [Abstract] [Full Text] [PDF]

				T. Wakabayashi and B. De Strooper Presenilins: Members of the {gamma}-Secretase Quartets, But Part-Time Soloists Too Physiology, August 1, 2008; 23(4): 194 - 204. [Abstract] [Full Text] [PDF]

				K. Schrenk-Siemens, S. Perez-Alcala, J. Richter, E. Lacroix, J. Rahuel, M. Korte, U. Muller, Y.-A. Barde, and M. Bibel Embryonic Stem Cell-Derived Neurons as a Cellular System to Study Gene Function: Lack of Amyloid Precursor Proteins APP and APLP2 Leads to Defective Synaptic Transmission Stem Cells, August 1, 2008; 26(8): 2153 - 2163. [Abstract] [Full Text] [PDF]

				S. Schobel, S. Neumann, M. Hertweck, B. Dislich, P.-H. Kuhn, E. Kremmer, B. Seed, R. Baumeister, C. Haass, and S. F. Lichtenthaler A Novel Sorting Nexin Modulates Endocytic Trafficking and {alpha}-Secretase Cleavage of the Amyloid Precursor Protein J. Biol. Chem., May 23, 2008; 283(21): 14257 - 14268. [Abstract] [Full Text] [PDF]

				D. D. Ikeda, Y. Duan, M. Matsuki, H. Kunitomo, H. Hutter, E. M. Hedgecock, and Y. Iino CASY-1, an ortholog of calsyntenins/alcadeins, is essential for learning in Caenorhabditis elegans PNAS, April 1, 2008; 105(13): 5260 - 5265. [Abstract] [Full Text] [PDF]

				T. L. Young-Pearse, J. Bai, R. Chang, J. B. Zheng, J. J. LoTurco, and D. J. Selkoe A Critical Function for -Amyloid Precursor Protein in Neuronal Migration Revealed by In Utero RNA Interference J. Neurosci., December 26, 2007; 27(52): 14459 - 14469. [Abstract] [Full Text] [PDF]

				M. S. Wolfe and S. Y. Guenette APP at a glance J. Cell Sci., September 15, 2007; 120(18): 3157 - 3161. [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help