. Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system. Nat Commun. 2013;4:2250. PubMed.

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  1. This is a spectacular study, linking lipid metabolism, membrane trafficking and Alzheimer's disease. It is carefully done, combining elegant cell biology in neurons with biochemistry. For me, the most important aspect of the study is that the findings suggest that in the absence of any genetic abnormalities in the retromer components, misregulation in lipid levels could phenocopy late-onset AD symptoms.

    The role of endocytosis in the generation of Aβ peptides was identified long ago (Koo et al., 1994;. Cataldo et al., , 1997(). We previously showed that Rab5-EEA1 positive endosomes are involved in the beta-secretase processing of APP (Rajendran et al., 2006; Rajendran et al., 2008). Wim Annaert's lab demonstrated that BACE1 traffics to the early endosomes via a Arf6 mediated pathway (Sannerud et al., 2011) and we showed in an earlier work that APP endocytosis depends on cholesterol and flotillin (Schneider et al., 2008). These studies established sorting of both APP and BACE1 to early endosomes as key events in the generation of Aβ. Now, the authors looked carefully at the role of endosomal lipids, such as phophatidylinositol-3-phosphate lipids, in the sorting of APP. They demonstrate that PI3P deficiency, as observed in AD brains and in the brains of APP transgenic mice, leads to enhanced amyloidogenic processing of APP. They attribute this to altered sorting of APP.

    The authors show that APP can be sorted to the intraluminal vesicles (ILVs) of multivesicular bodies (MVBs)- a process whereby membrane proteins are either marked for degradation via lysosomes or for the removal by secretion through exosomes. They show that APP, if ubiquitinated, can be sorted to these ILVs as a means for their removal from early endosomes, where they are processed by BACE1. Misregulation of this sorting to ILVs, due to PI3P deficiency or mutation in ubiquitination signals, leads to enhanced Aβ secretion, thus linking ILV sorting of APP to downregulation of amyloidogenic processing of the protein. Since PI3P levels are decreased in late-onset AD cases, this work offers a convincing explanation for the increased Aβ levels in AD. Interestingly, early work by Anne Cataldo and Ralph Nixon has shown that the early endosomes are enlarged in AD patient brains and the current work lends supportive evidence that PI3P deficiency could contribute to this abnormal morphology and decreased ILV sorting of APP.

    Of note, since the authors discover that APP is sorted to the intra-luminal vesicles (ILVs) of the multivesicular endosomes, it would be interesting to see if some of the APP is secreted via exosomes (the vesicles that are derived from the fusion of MVBs with the plasma membrane thereby releasing their ILVs as exosomes). Since Aβ has been shown to be released via exosomes (Rajendran et al., 2006), it would be interesting to see if the precursor protein is secreted via exosomes as well. Of course, an open question is what happens to beta and gamma-secretase sorting under these conditions? Interesting times ahead for more cell biology studies in AD.

    References:

    . Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem. 1994 Jul 1;269(26):17386-9. PubMed.

    . Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci. 1997 Aug 15;17(16):6142-51. PubMed.

    . Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11172-7. PubMed.

    . Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting. Science. 2008 Apr 25;320(5875):520-3. PubMed.

    . Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons. J Neurosci. 2008 Mar 12;28(11):2874-82. PubMed.

    . ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E559-68. PubMed.

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