The C‐terminal fragment of the Alzheimer's disease amyloid protein precursor is degraded by a proteasome‐dependent mechanism distinct from γ‐secretase

Nunan, Janelle; Shearman, Mark S.; Checler, Frédéric; Cappai, Roberto; Evin, Geneviève; Beyreuther, Konrad; Masters, Colin L.; Small, David H.

doi:10.1046/j.0014-2956.2001.02465.x

Cited by 117 publications

(123 citation statements)

References 40 publications

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“…1B), indicating that the lysosomal pathway is not responsible for the observed reduction in C83 levels. MG132 cell treatments resulted in accumulation of APP CTF␤ and A␤40, indicating that the proteasome plays a role in APP CTF␤ degradation (30). Similarly, calpain was previously implicated in the degradation of C83 and C99 and in the generation of A␤, particularly A␤42 (20,31).…”

Section: Resultsmentioning

confidence: 81%

Generation of the β-Amyloid Peptide and the Amyloid Precursor Protein C-terminal Fragment γ Are Potentiated by FE65L1

Chang

Tesco

Jeong

et al. 2003

Journal of Biological Chemistry

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Members of the FE65 family of adaptor proteins, FE65, FE65L1, and FE65L2, bind the C-terminal region of the amyloid precursor protein (APP). Overexpression of FE65 and FE65L1 was previously reported to increase the levels of ␣-secretase-derived APP (APPs␣). Increased ␤-amyloid (A␤) generation was also observed in cells showing the FE65-dependent increase in APPs␣. To understand the mechanism for the observed increase in both A␤ and APPs␣ given that ␣-secretase cleavage of a single APP molecule precludes A␤ generation, we examined the effects of FE65L1 overexpression on APP Cterminal fragments (APP CTFs). Our data show that FE65L1 potentiates ␥-secretase processing of APP CTFs, including the amyloidogenic CTF C99, accounting for the ability of FE65L1 to increase generation of APP Cterminal domain and A␤40. The FE65L1 modulation of these processing events requires binding of FE65L1 to APP and APP CTFs and is not because of a direct effect on ␥-secretase activity, because Notch intracellular domain generation is not altered by FE65L1. Furthermore, enhanced APP CTF processing can be detected in early endosome vesicles but not in endoplasmic reticulum or Golgi membranes, suggesting that the effects of FE65L1 occur at or near the plasma membrane. Finally, although FE65L1 increases APP C-terminal domain production, it does not mediate the APP-dependent transcriptional activation observed with FE65.Processing of the amyloid precursor protein (APP) 1 results in the generation of the amyloidogenic peptide, A␤, which plays a central role in the pathogenesis of Alzheimer's disease. Cleavage of C99, the APP C-terminal fragment derived from ␤-secretase processing of APP, by ␥-secretase generates the A␤ peptide. Furthermore, ␥-secretase cleavage of C99 and C83, the ␣-secretase derived APP C-terminal fragment (APP CTF), releases the APP C-terminal domain (AICD), a 6-kDa peptide also called CTF␥ or AID, that regulates transcription after translocation to the nucleus (1-4).The majority of proteins reported to bind the 47-amino acid intracellular region of APP (5-7), including the FE65 protein family members FE65, FE65L1, and FE65L2, bind the YENPTY sorting motif of APP via a phosphotyrosine interaction domain (PID/PTB). YENP is a clathrin-coated pit internalization domain required for trafficking of APP into the endocytic pathway (8, 9). Previous studies have shown that FE65 protein family members can alter the processing of APP by influencing APP trafficking. Increased maturation of APP and increased ␣-secretase-cleaved APP (APPs␣) secretion was observed in H4 neuroglioma cells induced for FE65L1 overexpression (10). Furthermore, enhanced secretion of APPs␣ and A␤ was reported in Madin-Darby canine kidney APP695 cells stably overexpressing FE65 (11). Cell surface APP levels were elevated in these cells, and increased routing of APP into the endocytic pathway from the plasma membrane was suggested to account for the observed increase in A␤ (11).The FE65 proteins are adaptor proteins that have three protein-protein interaction dom...

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Section: Resultsmentioning

confidence: 81%

Generation of the β-Amyloid Peptide and the Amyloid Precursor Protein C-terminal Fragment γ Are Potentiated by FE65L1

Chang

Tesco

Jeong

et al. 2003

Journal of Biological Chemistry

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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: 86%

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

Adlard¹,

Perreau²,

Pop³

et al. 2005

J. Neurosci.

696

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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“…Alternatively, lower CTF-beta may be associated with enhanced degradation and clearance mechanisms in DS that may subsequently be linked to the lack of Aβ plaque accumulation despite overexpression of full length APP. The pathways that may be involved with enhanced CTFbeta turnover in DS have yet to be determined but may involve the proteasome [42,44] and it is interesting to note that proteins involved with the 20S proteasome are increased in DS fetal brain tissue [11].…”

Section: Discussionmentioning

confidence: 99%

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

107

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Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alphasecretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Aβ) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Aβ degradation and clearance.

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The C‐terminal fragment of the Alzheimer's disease amyloid protein precursor is degraded by a proteasome‐dependent mechanism distinct from γ‐secretase

Cited by 117 publications

References 40 publications

Generation of the β-Amyloid Peptide and the Amyloid Precursor Protein C-terminal Fragment γ Are Potentiated by FE65L1

Generation of the β-Amyloid Peptide and the Amyloid Precursor Protein C-terminal Fragment γ Are Potentiated by FE65L1

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

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

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