. Sphingolipid storage affects autophagic metabolism of the amyloid precursor protein and promotes Abeta generation. J Neurosci. 2011 Feb 2;31(5):1837-49. PubMed.


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  1. This paper by Tamboli et al. is an interesting study that highlights the increasing number of lysosomal storage diseases (LSDs) that have elevated amounts of APP-CTFs and Aβ, and indicates the importance of maintaining efficient lysosomal flux as an anti-amyloidogenic mechanism. The central hypothesis of this study proposes that sphingolipid storage 1) affects autophagic metabolism of amyloid precursor protein, and 2) promotes Aβ generation. However, in a recent study conducted by our group (Boland et al., 2010), we found that macroautophagy does not directly regulate APP metabolism, and the accumulation of APP-CTFs and Aβ in brains of mice with three different glycosphingolipid (GSL) storage diseases (Niemann-Pick Type C1, GM1 gangliosidosis, and Sandhoff disease) is due to impaired lysosomal catabolism.

    In contrast to the starvation-induced autophagy approach used by Tamboli et al., which may alter the rate of APP endocytosis, we found that APP metabolism (full-length APP, APP-CTFs, and secreted Aβ) remained unchanged when autophagy was specifically activated by rapamycin in cultured neurons. This despite increased expression of LC3-II, a marker of autophagic vacuoles (AVs). While both studies report increases in LC3-II and APP-CTFs when lysosomal proteases are inhibited, the discrepancy we observed between these two markers in mouse models of GSL storage diseases versus rapamycin-treated neurons (with or without lysosomal inhibitors) suggests that APP is not directly metabolized in autophagosomes. Instead, endosomal-lysosomal proteolysis is more likely to regulate APP catabolism.


    . Macroautophagy is not directly involved in the metabolism of amyloid precursor protein. J Biol Chem. 2010 Nov 26;285(48):37415-26. PubMed.

  2. This paper by Tamboli at al. is a very interesting study supporting the potential role of autophagy in APP turnover and degradation. The authors show a connection between sphingolipid accumulation and a disturbance in autophagic flux, which in turn impairs the proper clearance of APP-CTFs and enhances the production of β amyloid. Work from our lab published in 2008 and 2010 demonstrated the importance of autophagy and Beclin 1, a protein involved in autophagy initiation and autophagosome maturation, in APP metabolism, both in vivo (Pickford et al., 2008) and in vitro (Jaeger et al., 2010). We suggested that—based on our mouse, cell culture, and human data—autophagy is an important degradative pathway for APP catabolism and of potential importance in Alzheimer's disease pathology. The data in this paper by Tamboli et al. strongly support that idea.

    The endosomal-lysosomal system and the autophagy system appear to both fulfill certain aspects of APP catabolism, and different experimental settings seem to sometimes favor one system over the other (see above comment by Barry Boland on this topic and an ARF related news story). However, the combination of genetic evidence (Beclin 1 knockdown and overexpression), pharmacological intervention (Rapamycin, Thapsigargin, Bafilomycin A, etc.), and now sphingolipid levels appears to support that macroautophagy might indeed play a crucial role in APP turnover and β amyloid production.

    Is autophagy the only degradative pathway for APP and β amyloid? Probably not. It seems likely that the cellular machinery provides parallel degradative pathways for APP and its catabolites. But since endosomal-lysosomal degradation and autophagy are intimately connected and share a common endpoint (the lysosome), it appears that both pathways should be considered as important intervention points for the modulation of APP in future Alzheimer's disease therapies.


    . Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS One. 2010;5(6):e11102. PubMed.

    . The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest. 2008 Jun;118(6):2190-9. PubMed.

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  1. A Surfeit of Sphingolipids Sours Aβ Digestion