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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, April 19, 2006, 26(16):4277-4288; doi:10.1523/JNEUROSCI.5078-05.2006

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 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 (24) Citing Articles via Google Scholar Google Scholar Articles by Almeida, C. G. Articles by Gouras, G. K. Search for Related Content PubMed PubMed Citation Articles by Almeida, C. G. Articles by Gouras, G. K. Pubmed/NCBI databases Substance via MeSH

 Previous Article  |  Next Article 

Cellular/Molecular
-Amyloid Accumulation Impairs Multivesicular Body Sorting by Inhibiting the Ubiquitin-Proteasome System

Claudia G. Almeida, Reisuke H. Takahashi, and Gunnar K. Gouras

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021

Correspondence should be addressed to Dr. Gunnar K. Gouras, Laboratory of Alzheimer’s Disease Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, Room A-569, New York, NY 10021. Email: gkgouras{at}med.cornell.edu

Increasing evidence links intraneuronal -amyloid (A₄₂) accumulation with the pathogenesis of Alzheimer’s disease (AD). In A precursor protein (APP) mutant transgenic mice and in human AD brain, progressive intraneuronal accumulation of A₄₂ occurs especially in multivesicular bodies (MVBs). We hypothesized that this impairs the MVB sorting pathway. We used the trafficking of the epidermal growth factor receptor (EGFR) and TrkB receptor to investigate the MVB sorting pathway in cultured neurons. We report that, during EGF stimulation, APP mutant neurons demonstrated impaired inactivation, degradation, and ubiquitination of EGFR. EGFR degradation is dependent on translocation from MVB outer to inner membranes, which is regulated by the ubiquitin-proteasome system (UPS). We provide evidence that A accumulation in APP mutant neurons inhibits the activities of the proteasome and deubiquitinating enzymes. These data suggest a mechanism whereby A accumulation in neurons impairs the MVB sorting pathway via the UPS in AD.

Key words: Alzheimer’s disease; endocytosis; neuron; EGFR; TrkB; endosome

---

Received Sept. 9, 2005; revised Jan. 27, 2006; accepted March 17, 2006.

Correspondence should be addressed to Dr. Gunnar K. Gouras, Laboratory of Alzheimer’s Disease Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, Room A-569, New York, NY 10021. Email: gkgouras{at}med.cornell.edu

This article has been cited by other articles:

				J. R. Steinerman, M. Irizarry, N. Scarmeas, S. Raju, J. Brandt, M. Albert, D. Blacker, B. Hyman, and Y. Stern Distinct Pools of {beta}-Amyloid in Alzheimer Disease-Affected Brain: A Clinicopathologic Study Arch Neurol, July 1, 2008; 65(7): 906 - 912. [Abstract] [Full Text] [PDF]

				R. A. Nixon Autophagy, amyloidogenesis and Alzheimer disease J. Cell Sci., December 1, 2007; 120(23): 4081 - 4091. [Abstract] [Full Text] [PDF]

				A. Li, Z. Xie, Y. Dong, K. M. McKay, M. L. McKee, and R. E. Tanzi Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes Hum. Mol. Genet., November 1, 2007; 16(21): 2626 - 2639. [Abstract] [Full Text] [PDF]

				E. Repetto, I.-S. Yoon, H. Zheng, and D. E. Kang Presenilin 1 Regulates Epidermal Growth Factor Receptor Turnover and Signaling in the Endosomal-Lysosomal Pathway J. Biol. Chem., October 26, 2007; 282(43): 31504 - 31516. [Abstract] [Full Text] [PDF]

				R. Sitia, G. Palladini, and G. Merlini Bortezomib in the treatment of AL amyloidosis: targeted therapy? Haematologica, October 1, 2007; 92(10): 1302 - 1307. [Full Text] [PDF]

				D. Tampellini, J. Magrane, R. H. Takahashi, F. Li, M. T. Lin, C. G. Almeida, and G. K. Gouras Internalized Antibodies to the Abeta Domain of APP Reduce Neuronal Abeta and Protect against Synaptic Alterations J. Biol. Chem., June 29, 2007; 282(26): 18895 - 18906. [Abstract] [Full Text] [PDF]

				C. Goldsbury, E. Thies, S. Konzack, and E.-M. Mandelkow Quantification of Amyloid Precursor Protein and Tau for the Study of Axonal Traffic Pathways J. Neurosci., March 28, 2007; 27(13): 3357 - 3363. [Full Text] [PDF]

				M. Miranda, K. R. Dionne, T. Sorkina, and A. Sorkin Three Ubiquitin Conjugation Sites in the Amino Terminus of the Dopamine Transporter Mediate Protein Kinase C-dependent Endocytosis of the Transporter Mol. Biol. Cell, January 1, 2007; 18(1): 313 - 323. [Abstract] [Full Text] [PDF]

				M. J. O. Widenbrant, J. Rajadas, C. Sutardja, and G. G. Fuller Lipid-Induced {beta}-Amyloid Peptide Assemblage Fragmentation Biophys. J., December 1, 2006; 91(11): 4071 - 4080. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help