Amyloid peptide attenuates the proteasome activity in neuronal cells

Oh, Sang-Soo; Hong, Hyun Seok; Hwang, Enmi; Sim, Hae Jin; Lee, Woojin; Shin, Su Jeon; Mook‐Jung, Inhee

doi:10.1016/j.mad.2005.07.006

Cited by 135 publications

(95 citation statements)

References 41 publications

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“…Although the cellular function of ubiquilin remains unclear, it is known to contain an ubiquitin-like domain in its N terminus and an ubiquitinassociated domain in its C terminus and therefore could interact both with ubiquitin ligases and the proteasome (Kleijnen et al, 2003). Ubiquitin is well known to be increased especially in dystrophic neurites of human AD and of mouse models of ␤-amyloidosis (Blanchard et al, 2003), an aberrant form of ubiquitin was reported to accumulate in human AD and Down syndrome brains (van Leeuwen et al, 1998), A␤ was reported to decrease proteasome activity in cultured neurons (Lopez Salon et al, 2003), and proteasome activity was described to be reduced in the brains of Tg2576 mice (Oh et al, 2005) and human AD (Keller et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

β-Amyloid Accumulation Impairs Multivesicular Body Sorting by Inhibiting the Ubiquitin-Proteasome System

Almeida¹,

2006

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Increasing evidence links intraneuronal ␤-amyloid (A␤ 42 ) 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 A␤ 42 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.

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Section: Discussionmentioning

confidence: 99%

β-Amyloid Accumulation Impairs Multivesicular Body Sorting by Inhibiting the Ubiquitin-Proteasome System

Almeida¹,

2006

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“…Indeed, the authors hypothesize that the inhibition of the UPS by A␤ impairs the endocytic trafficking of neuronal receptors and thereby may be the cause of synaptic dysfunction in AD. Furthermore, several others studies suggest that an inhibition of the proteasome leads to an increase of A␤ levels [122,123]. Recent studies by LaFerla's group have shown proteasome inhibition in the 3xTg-AD mice at ages at which oligomeric A␤ accumulation is seen within neuronal cell bodies [123,124].…”

Section: Intracellular A␤ Oligomer Toxicitymentioning

confidence: 99%

Molecular Mechanisms of Amyloid Oligomers Toxicity

Kayed

Lasagna‐Reeves

2012

JAD

315

276

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Abstract. Amyloid oligomers have emerged as the most toxic species of amyloid-␤ (A␤). This hypothesis might explain the lack of correlation between amyloid plaques and memory impairment or cellular dysfunction. However, despite the numerous published research articles supporting the critical role A␤ oligomers in synaptic dysfunction and cell death, the exact definition and mechanism of amyloid oligomers formation and toxicity still elusive. Here we review the evidence supporting the many molecular mechanisms proposed for amyloid oligomers toxicity and suggest that the complexity and dynamic nature of amyloid oligomers may be responsible for the discrepancy among these mechanisms and the proposed cellular targets for amyloid oligomers.

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“…have shown that Aβ protein inhibit the proteasome [64][65][66] and that this inhibition may be mediated by Aβ oligomers. 67 Furthermore, extracellular aggregates of another amyloidogenic protein, human islet amyloid polypeptide, impair the ubiquitin-proteasome pathway resulting in ER stress-mediated pancreatic β-cell apoptosis.…”

confidence: 99%