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Comments on Paper and Primary News |
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Primary News: APP in Pieces: βCTF implicated in Endosome Dysfunction
Comment by: Philip Wong
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Submitted 8 January 2010
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Posted 8 January 2010
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If it’s true that accumulation of APP-βCTFs in the brain is toxic in AD, it would suggest that lowering the activity of γ-secretase alone may not be sufficient to deal with both problems of accumulation of Aβ and that of APP-βCTFs. Simultaneous reduction of both secretases would be predicted to be more efficacious, and such combination therapy also highlights the values of coordinately reducing all APP derivatives in a balanced manner.  View all comments by Philip Wong |
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Comment by: Andre Delacourte, ARF Advisor
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Submitted 24 January 2010
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Posted 26 January 2010
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 I recommend this paper
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Comment by: Donald C. Lo, ARF Advisor
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Submitted 24 January 2010
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Posted 26 January 2010
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I recommend this paper
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Primary News: APP in Pieces: βCTF implicated in Endosome Dysfunction
Comment by: Virgil Muresan, Zoia Muresan
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Submitted 25 January 2010
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Posted 26 January 2010
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It is established that overexpression of APP, such as in Down syndrome, leads to endosome dysfunction. The article by Jiang et al. (1) now elegantly shows that the endosomal abnormalities are not caused by increased levels of Aβ. Rather, it is the presence of the precursor polypeptide of Aβ, the βCTF, which correlates with the endosomal dysfunction. We reported that APP species (APP and/or CTFs) that accumulate at the endosomes of APP overexpressing neurons in culture show increased phosphorylation at Thr668 (numbering in APP695) (2). We found that this increased phosphorylation requires the activity of Cdk5. It now remains to find out whether the phosphorylation of the endosome-targeted APP and βCTF plays an active role in inflicting endosomal abnormalities, or it is rather these abnormalities that trigger this phosphorylation event.
This article by Jiang et al. (1) is adding important data that indicate that APP fragments other than Aβ can be toxic to cells. It appears that the toxicity, and in many cases the function of APP, is mediated by the polypeptides derived by...
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It is established that overexpression of APP, such as in Down syndrome, leads to endosome dysfunction. The article by Jiang et al. (1) now elegantly shows that the endosomal abnormalities are not caused by increased levels of Aβ. Rather, it is the presence of the precursor polypeptide of Aβ, the βCTF, which correlates with the endosomal dysfunction. We reported that APP species (APP and/or CTFs) that accumulate at the endosomes of APP overexpressing neurons in culture show increased phosphorylation at Thr668 (numbering in APP695) (2). We found that this increased phosphorylation requires the activity of Cdk5. It now remains to find out whether the phosphorylation of the endosome-targeted APP and βCTF plays an active role in inflicting endosomal abnormalities, or it is rather these abnormalities that trigger this phosphorylation event.
This article by Jiang et al. (1) is adding important data that indicate that APP fragments other than Aβ can be toxic to cells. It appears that the toxicity, and in many cases the function of APP, is mediated by the polypeptides derived by proteolytic processing from this parental protein. Instead of being “e pluribus unum,” APP is “e unum pluribus.”
References:
1. Jiang, Y., et al., Alzheimer's-related endosome dysfunction in Down syndrome is A{beta}-independent but requires APP and is reversed by BACE-1 inhibition. Proc Natl Acad Sci U S A, 2009. Abstract
2. Muresan, Z. and V. Muresan, The amyloid-beta precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration. Mol Biol Cell, 2007. 18(10): p. 3835-44. Abstract
View all comments by Virgil Muresan
View all comments by Zoia Muresan |
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Comment by: George Perry (Disclosure)
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Submitted 5 March 2010
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Posted 8 March 2010
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I recommend this paper
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REAGENTS/MATERIAL:
Immunofluorescence Labeling. Cells were washed with PBS and fixed with 4% paraformaldehyde at room temperature for 20 min
and probed with C1/6.1 (against the C terminus of APP),
N25 (against βCTF and Aβ),
or anti-SOD1 (Santa Cruz Biotechnology Inc).
Transfected fibroblasts were identified with
anti-GFP antibody (Invitrogen)
or anti-RFP (Abcam),
whereas mouse monoclonal anti-EEA1 (14) (BD Biosicences) was used to examine phenotypic changes in early endosomes.
Western Blot Analysis. Lysate was collected from fibroblasts, and equal amounts of protein were sized by SDS/PAGE as described previously. Various antibodies, including C1/6.1,
mouse monoclonal anti-APP (6E10) (Covance),
anti-SOD1, mouse monoclonal anti-β-actin (Sigma),
anti-GAPDH (Santa Cruz),
and anti-transferrin (AbCam) were used to detect levels of these specific proteins
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