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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, July 4, 2007, 27(27):7141-7153; doi:10.1523/JNEUROSCI.4599-06.2007

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 (2) Citing Articles via Google Scholar Google Scholar Articles by Laifenfeld, D. Articles by Neve, R. L. Search for Related Content PubMed PubMed Citation Articles by Laifenfeld, D. Articles by Neve, R. L.

 Previous Article  |  Next Article 

Neurobiology of Disease
Rab5 Mediates an Amyloid Precursor Protein Signaling Pathway That Leads to Apoptosis

Daphna Laifenfeld,¹ Lucas J. Patzek,¹ Donna L. McPhie,¹ Yuzhi Chen,² Yona Levites,³ Anne M. Cataldo,¹ and Rachael L. Neve¹

¹Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, ²Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, and ³Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224

Correspondence should be addressed to either Daphna Laifenfeld or Rachael L. Neve, MRC 223, McLean Hospital, 115 Mill Street, Belmont, MA 02478. Email: dlaifenfeld{at}mclean.harvard.edu or Email: neve{at}helix.mgh.harvard.edu

Alzheimer's disease (AD) involves activation of apoptotic pathways that may be regulated through signaling cascades initiated by the amyloid precursor protein (APP). Enlarged endosomes have been observed in postmortem AD brains at very early stages of the disease. We show here that exogenous expression of a familial AD (FAD) mutant of APP or of the APP binding protein APP–BP1 in neurons causes enlargement of early endosomes, increased receptor-mediated endocytosis via a pathway dependent on APP–BP1 binding to APP, and apoptosis. Levels of both APP–BP1 and Rab5 are elevated in early endosomes in cortical embryonic neurons expressing APP(V642I) or APP–BP1, in cultured skin fibroblast cells from Down syndrome subjects, and in postmortem hippocampal tissue of individuals with AD. Indeed, Rab5 was found to bind specifically to APP–BP1, between amino acids 443 and 479. Inhibition of Rab5 or dynamin activity, but not of Eps15 (epidermal growth factor receptor pathway substrate 15) activity, rescued neurons from apoptosis induced by either APP(V642I) or APP–BP1, without affecting levels of intracellular or secreted amyloid-ß (Aß). Induction of Rab5 activity via expression of a constitutively active mutant led to an increase in neuronal apoptosis more than twice that attributable to induction of endosome enlargement via a Rab5-independent mechanism, regardless of Aß production. Together, these findings suggest that Rab5 activation via an APP/APP–BP1-initiated signaling pathway mediates neuronal apoptosis caused by FAD mutants of APP and that, within this pathway, Rab5 has a specific role in signaling that is distinct from, although not independent of, its role in trafficking.

Key words: Alzheimer's disease; endosomes; amyloid precursor protein; apoptosis; APP–BP1; Rab5

---

Received Oct. 23, 2006; revised April 11, 2007; accepted May 1, 2007.

Correspondence should be addressed to either Daphna Laifenfeld or Rachael L. Neve, MRC 223, McLean Hospital, 115 Mill Street, Belmont, MA 02478. Email: dlaifenfeld{at}mclean.harvard.edu or Email: neve{at}helix.mgh.harvard.edu

This article has been cited by other articles:

				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]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help