RT Journal Article
SR Electronic
T1 β-Amyloid Accumulation Impairs Multivesicular Body Sorting by Inhibiting the Ubiquitin-Proteasome System
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4277
OP 4288
DO 10.1523/JNEUROSCI.5078-05.2006
VO 26
IS 16
A1 Claudia G. Almeida
A1 Reisuke H. Takahashi
A1 Gunnar K. Gouras
YR 2006
UL http://www.jneurosci.org/content/26/16/4277.abstract
AB Increasing evidence links intraneuronal β-amyloid (Aβ42) accumulation with the pathogenesis of Alzheimer’s disease (AD). In Aβ precursor protein (APP) mutant transgenic mice and in human AD brain, progressive intraneuronal accumulation of Aβ42 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 Aβ accumulation in APP mutant neurons inhibits the activities of the proteasome and deubiquitinating enzymes. These data suggest a mechanism whereby Aβ accumulation in neurons impairs the MVB sorting pathway via the UPS in AD.