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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, January 11, 2006, 26(2):418-428; doi:10.1523/JNEUROSCI.3882-05.2006

This Article Full Text Full Text (PDF) 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 ISI 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 ISI Web of Science (29) Citing Articles via Google Scholar Google Scholar Articles by Spoelgen, R. Articles by Hyman, B. T. Search for Related Content PubMed PubMed Citation Articles by Spoelgen, R. Articles by Hyman, B. T.

 Previous Article  |  Next Article 

Neurobiology of Disease
Interaction of the Cytosolic Domains of sorLA/LR11 with the Amyloid Precursor Protein (APP) and -Secretase -Site APP-Cleaving Enzyme

Robert Spoelgen,¹ Christine A. F. von Arnim,¹ Anne V. Thomas,¹ Ithan D. Peltan,¹ Mirjam Koker,¹ Amy Deng,¹ Michael C. Irizarry,¹ Olav M. Andersen,² Thomas E. Willnow,² and Bradley T. Hyman¹

¹Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, and ²Max Delbrück Center for Molecular Medicine, D-13125 Berlin, Germany

sorLA is a recently identified neuronal receptor for amyloid precursor protein (APP) that is known to interact with APP and affect its intracellular transport and processing. Decreased levels of sorLA in the brain of Alzheimer's disease (AD) patients and elevated levels of amyloid- peptide (A) in sorLA-deficient mice point to the importance of the receptor in this neurodegenerative disorder. We analyzed APP cleavage in an APP-shedding assay and found that both sorLA and, surprisingly, a sorLA tail construct inhibited APP cleavage in a -site APP-cleaving enzyme (BACE)-dependent manner. In line with this finding, sorLA and the sorLA tail significantly reduced secreted A levels when BACE was overexpressed, suggesting that sorLA influences-cleavage. To understand the effect of sorLA on APP cleavage by BACE, we analyzed whether sorLA interacts with APP and/or BACE. Because both full-length sorLA and sorLA C-terminal tail constructs were functionally relevant for APP processing, we analyzed sorLA–APP for a potential cytoplasmatic interaction domain. sorLA and C99 coimmunoprecipitated, pointing toward the existence of a new cytoplasmatic interaction site between sorLA and APP. Moreover, sorLA and BACE also coimmunoprecipitate. Thus, sorLA interacts both with BACE and APP and might therefore directly affect BACE–APP complex formation. To test whether sorLA impacts BACE–APP interactions, we used a fluorescence resonance energy transfer assay to evaluate BACE–APP interactions in cells. We discovered that sorLA significantly reduced BACE–APP interactions in Golgi. We postulate that sorLA acts as a trafficking receptor that prevents BACE–APP interactions and hence BACE cleavage of APP.

Key words: sorLA; Alzheimer's disease; amyloid-; BACE; amyloid precursor protein; LR11

---

Received Sep 13, 2005; revised November 9, 2005; accepted November 14, 2005.

This article has been cited by other articles:

				M. Rohe, A.-S. Carlo, H. Breyhan, A. Sporbert, D. Militz, V. Schmidt, C. Wozny, A. Harmeier, B. Erdmann, K. R. Bales, et al. Sortilin-related Receptor with A-type Repeats (SORLA) Affects the Amyloid Precursor Protein-dependent Stimulation of ERK Signaling and Adult Neurogenesis J. Biol. Chem., May 23, 2008; 283(21): 14826 - 14834. [Abstract] [Full Text] [PDF]

				A. Schneider, L. Rajendran, M. Honsho, M. Gralle, G. Donnert, F. Wouters, S. W. Hell, and M. Simons Flotillin-Dependent Clustering of the Amyloid Precursor Protein Regulates Its Endocytosis and Amyloidogenic Processing in Neurons J. Neurosci., March 12, 2008; 28(11): 2874 - 2882. [Abstract] [Full Text] [PDF]

				Q.-L. Ma, B. Teter, O. J. Ubeda, T. Morihara, D. Dhoot, M. D. Nyby, M. L. Tuck, S. A. Frautschy, and G. M. Cole Omega-3 Fatty Acid Docosahexaenoic Acid Increases SorLA/LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer's Disease (AD): Relevance to AD Prevention J. Neurosci., December 26, 2007; 27(52): 14299 - 14307. [Abstract] [Full Text] [PDF]

				V. Schmidt, A. Sporbert, M. Rohe, T. Reimer, A. Rehm, O. M. Andersen, and T. E. Willnow SorLA/LR11 Regulates Processing of Amyloid Precursor Protein via Interaction with Adaptors GGA and PACS-1 J. Biol. Chem., November 9, 2007; 282(45): 32956 - 32964. [Abstract] [Full Text] [PDF]

				M. S. Nielsen, C. Gustafsen, P. Madsen, J. R. Nyengaard, G. Hermey, O. Bakke, M. Mari, P. Schu, R. Pohlmann, A. Dennes, et al. Sorting by the Cytoplasmic Domain of the Amyloid Precursor Protein Binding Receptor SorLA Mol. Cell. Biol., October 1, 2007; 27(19): 6842 - 6851. [Abstract] [Full Text] [PDF]

				T. Wahle, D. R. Thal, M. Sastre, A. Rentmeister, N. Bogdanovic, M. Famulok, M. T. Heneka, and J. Walter GGA1 Is Expressed in the Human Brain and Affects the Generation of Amyloid {beta}-Peptide J. Neurosci., December 6, 2006; 26(49): 12838 - 12846. [Abstract] [Full Text] [PDF]

				C. A. F. von Arnim, R. Spoelgen, I. D. Peltan, M. Deng, S. Courchesne, M. Koker, T. Matsui, H. Kowa, S. F. Lichtenthaler, M. C. Irizarry, et al. GGA1 Acts as a Spatial Switch Altering Amyloid Precursor Protein Trafficking and Processing J. Neurosci., September 27, 2006; 26(39): 9913 - 9922. [Abstract] [Full Text] [PDF]

				H.-S. Hoe, L. A. Magill, S. Guenette, Z. Fu, S. Vicini, and G. W. Rebeck FE65 Interaction with the ApoE Receptor ApoEr2 J. Biol. Chem., August 25, 2006; 281(34): 24521 - 24530. [Abstract] [Full Text] [PDF]

				C. Bohm, N. M. Seibel, B. Henkel, H. Steiner, C. Haass, and W. Hampe SorLA Signaling by Regulated Intramembrane Proteolysis J. Biol. Chem., May 26, 2006; 281(21): 14547 - 14553. [Abstract] [Full Text] [PDF]

				P. J. Hallett, R. Spoelgen, B. T. Hyman, D. G. Standaert, and A. W. Dunah Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking. J. Neurosci., April 26, 2006; 26(17): 4690 - 4700. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help