. Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition. Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1630-5. PubMed.

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  1. 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
  2. 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.”

    View all comments by Virgil Muresan

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  1. APP in Pieces: βCTF implicated in Endosome Dysfunction