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