Relationship between β-amyloid degradation and the 26S proteasome in neural cells

Salon, M Lopez; Pasquini, Laura; Moreno, Marcos Besio; Pasquini, Juana M.; Soto, Eduardo F.

doi:10.1016/s0014-4886(02)00060-2

Cited by 135 publications

(76 citation statements)

References 64 publications

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“…Because physical activity modulates a multitude of gene products at both the mRNA and protein level, inducing anatomical, neurochemical, and electrophysiological changes that promote neuronal plasticity (Cotman and Berchtold, 2002), it is possible that multiple pathways may be activated to regulate amyloid levels either directly or indirectly. One possibility, for example, is that there is an exercise-induced upregulation of proteasome activity, as reported previously in muscle (Radak et al, 2000), that can mediate the degradation of the proteolytic fragments of APP (Nunan et al, 2001(Nunan et al, , 2003Lopez Salon et al, 2003;Schmitz et al, 2004). A more likely scenario, however, is that exercise is modulating APP metabolism directly (for review, see Turner et al, 2003) by increases in neuronal activity (Lee et al, 2003).…”

Section: Discussionmentioning

confidence: 87%

Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease

Adlard¹,

Perreau²,

Pop³

et al. 2005

J. Neurosci.

688

454

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-␤ (A␤) plaques in the frontal cortex (38%; p ϭ 0.018), the cortex at the level of the hippocampus (53%; p ϭ 0.0003), and the hippocampus (40%; p ϭ 0.06). This was associated with decreased cortical A␤1-40 (35%; p ϭ 0.005) and A␤1-42 (22%; p ϭ 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [for ␣-Cterminal fragment (␣-CTF), 54% and p ϭ 0.04; for ␤-CTF, 35% and p ϭ 0.03]. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant ( p Ͻ 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.

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Section: Discussionmentioning

confidence: 87%

Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease

Adlard¹,

Perreau²,

Pop³

et al. 2005

J. Neurosci.

688

454

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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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“…39 Regarding A␤ clearance it has been shown that A␤ can be degraded by the proteasome and it has been proposed that the normal proteolytic removal of A␤ could be affected in AD. 40 Hence, the up-regulation of a subunit of the 26S proteasome (Psmc4) and an activator of the 20S proteasome (Psme4) may have improved the abil- …”

Section: Proteasomal Degradationmentioning

confidence: 99%

Reduction of Amyloid Angiopathy and Aβ Plaque Burden after Enriched Housing in TgCRND8 Mice

Ambrée

Leimer

Herring

et al. 2006

The American Journal of Pathology

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Alzheimer's disease (AD) is the most prevalent form of senile dementia worldwide. It is characterized by two major histological hallmarks: senile plaques, ie, extracellular deposits mainly consisting of ␤-amyloid (A␤), and neurofibrillary tangles, ie, intracellular accumulations of hyperphosphorylated tau protein.1 AD patients show progressing cognitive decline as well as noncognitive behavioral symptoms such as wandering, sleep disturbance, and physical aggression.2 There are various risk factors for AD including age, family history, or apolipoprotein E 4 genotype.3 Epidemiological studies additionally suggest that the amount of time spent on intellectual and physical activities negatively correlates with the extent of cognitive decline and even risk of developing AD. 4,5 Although it cannot be excluded that lower activity levels are early subclinical symptoms, one should consider them also as a risk factor. In line with this assumption is the use of cognitive training as a rehabilitative measure resulting in deceleration of dementia progress. However, the underlying molecular pathways are essentially unknown.In laboratory rodents cognitive, physical, and social stimulation can be regulated by altering housing conditions. It is well established that living in an enriched environment provided by additional structural or social stimuli may increase locomotor and exploratory activity, improve learning and memory performance, increase dendritic sprouting and synapse formation in the neocortex and hippocampus as well as neurogenesis in the dentate gyrus, 6 and affects behavioral, endocrinological, and immunological parameters.7 Environmental enrichment also facilitates recovery from acute brain lesions,

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Relationship between β-amyloid degradation and the 26S proteasome in neural cells

Cited by 135 publications

References 64 publications

Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease

Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease

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

Reduction of Amyloid Angiopathy and Aβ Plaque Burden after Enriched Housing in TgCRND8 Mice

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